2,3-dihydrobenzo[1,4] dioxin-2-ylmethyl derivatives as alpha2c antagonists for use in the treatment of peripheric and central nervous system diseases

ABSTRACT

Compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             wherein X, Z, R 1 -R 4 , and m are as defined in the claims, exhibit alpha2C antagonistic activity, and are thus useful as alpha2C antagonists. Methods for the treatment of diseases and conditions of the peripheric system and the central nervous system are also disclosed.

FIELD OF THE INVENTION

The present invention relates to pharmacologically active 3-substituted1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles, or pharmaceuticallyacceptable salts and esters thereof, as well as to pharmaceuticalcompositions comprising them and to their use as alpha2C antagonists.

BACKGROUND OF THE INVENTION

It is generally known and accepted in the art that compounds exhibitingalpha adrenergic activity may be used for the treatment of a widevariety of diseases and conditions of the peripheric system and thecentral nervous system (CNS).

The alpha adrenergic receptors can be divided on a pharmacological basisinto alpha1 and alpha2 adrenoceptors, which can both be further dividedinto subtypes. Three genetically encoded subtypes, namely alpha2A,alpha2B, and alpha2C adrenoceptors, have been discovered in human. Afourth pharmacologically defined subtype, namely alpha2D adrenoceptor,is known in some other mammals and in rodents. It corresponds to thegenetically defined alpha2A adrenoceptor.

The alpha2 adrenoceptor subtypes have distinct tissue distributions andfunctional roles. For instance, while alpha2A adrenoceptors are widelyexpressed in various tissues, alpha2C adrenoceptors are concentrated inthe CNS and appear to play a role in the modulation of specific CNSmediated behavioral and physiological responses.

Some compounds that are non-specific for any of the above-mentionedalpha2 subtypes and some compounds that are specific for certain alpha2subtypes are known in the art. For example, atipamezole disclosed in EP183 492 A1 (compound XV at page 13) is a non-specific alpha2 antagonist.Compounds that are selective antagonists for the alpha2C subtype and areuseful for the treatment of mental illness, e.g. mental disturbanceinduced by stress, are described in U.S. Pat. No. 5,902,807. Suchcompounds are, for example, MK-912 and BAM-1303 Imidazole derivativeshaving agonist-like activity for alpha2B or 2B/2C adrenoceptors aredisclosed in WO 99/28300. Quinoline derivatives useful as alpha2antagonists are disclosed in WO 01/64645 and WO 2004/067513.Arylquinolizine derivatives useful as alpha2 antagonists are disclosedin WO 03/082866.

In order to be able to reduce the risk of adverse events duringtreatment, an enhanced selectivity of the alpha2 antagonists would bedesirable. For example, the use of non-selective alpha2 antagonists isattributed with side effects, such as increases in blood pressure, heartrate, salivary secretion, gastrointestinal secretion, and anxiety. Alsoan enhanced potency of the alpha2C antagonists would be desirable, inorder to be able to reduce the dose needed.

As to known 3-substituted1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles,1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-[1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-yl)-ethyl]-3,5-dimethyl-piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine,1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine,1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine,and1-[1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-yl)-ethyl]-3,5-dimethyl-piperidinehave been disclosed in WO 90/02122.1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acidmethyl ester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-oxo-piperidine-3-carboxylicacid methyl ester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid methyl ester, and1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid methyl ester have been disclosed in U.S. Pat. No. 4,957,928.2-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolineand2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehave been disclosed in DD 250 930 A1.2-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolinehas been disclosed in J. Org. Chem., 26 (1961) 339.1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl-3-(3-trifluoromethyl-phenyl)-pyrrolidinehas been disclosed in U.S. Pat. No. 3,644,414.

SUMMARY OF THE INVENTION

An object of the present invention is to provide further alpha2Cantagonists that can be used for the treatment of diseases or conditionsof the peripheric or central nervous system wherein alpha2C antagonistsare indicated to be useful. Accordingly, an object of the presentinvention is to provide further compounds to be used as alpha2Cantagonists in the treatment of mammals. Furthermore, pharmaceuticalcompositions comprising the present compounds are provided.

The alpha2 antagonists of the present invention have an improvedselectivity for the alpha2C adrenoceptor subtype and/or an enhancedpotency.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel alpha2C antagonists having thegeneral formula I,

wherein

X is C(R₅)(R₆) or C(R₇)(R₈);

Z is —[C(R₄)₂]_(n)— or a single bond;R₁ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, halo(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C═O)—, CN, NO₂, NH₂, mono- or di(C₁-C₆)alkylamino orcarboxy;R₂ is, independently at each occurrence, H or (C₁-C₆)alkyl;R₃ is, independently at each occurrence, H or (C₁-C₆)alkyl;R₄ is, independently at each occurrence, H, hydroxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₂-C₆)alkenyloxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl;or R₄ and R₄ both attached to the same carbon ring atom form, togetherwith the carbon ring atom to which they are attached, a —C═O)— group;R₅ is H or hydroxy;or R₄ and R₅ attached to adjacent carbon ring atoms form a bond betweenthe carbon ring atoms to which they are attached;R₆ is phenyl unsubstituted or substituted with 1 or 2 substituent(s) R₉;R₇ is H, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy-(C═O)—;or R₄ and R₅ attached to adjacent carbon ring atoms form a bond betweenthe carbon ring atoms to which they are attached;R₈ is hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy, halogen,hydroxy(C₁-C₆)allyl, halo(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl,hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₂-C₆)alkenyloxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy, hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—N(R₁₀)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, CN, NO₂,(R₁₀)₂N—, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)—,(R₁₀)₂N—(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl, carboxy, R₁₁—(O═S═O)—,R₁₁-(O═S═O)—O— or (C₁-C₆)alkoxy-(C₁-C₆)alkoxy;or R₄ and R₈ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed phenylring, wherein said phenyl ring is unsubstituted or substituted with 1 or2 substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkoxy-(C═O)—;or R₄ and R₈ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed 5 or 6membered saturated or unsaturated carbocyclic ring or a condensed 5 or 6membered saturated or unsaturated heterocyclic ring containing 1 or 2heteroatom(s) selected from N, O, and S, wherein said carbocyclic orheterocyclic ring is unsubstituted or substituted with 1 or 2substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C═O)— or oxo;or R₇ and R₈ form, together with the carbon ring atom to which they areattached, a 5 or 6 membered saturated carbocyclic ring or a 5 or 6membered saturated heterocyclic ring containing 1 or 2 heteroatom(s)selected from N, O, and S, wherein said carbocyclic or heterocyclic ringis unsubstituted or substituted with 1 or 2 substituent(s) eachindependently being hydroxy, (C₁-C₆)alkyl or oxo;R₉ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl, hydroxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₂-C₆)alkenyloxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkoxy-(C═O)—, (C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy, hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)allyl-S—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₁)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(O═S=O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—N(R₁₀)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, NO₂, (R₁₀)₂N—, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)—,(R₁₀)₂N—(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl, carboxy, R₁₁-(O═S═O)—or R₁₁—(O═S═O)—O—;or R₉ and R₉ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed phenylring, a condensed 5 or 6 membered unsaturated carbocyclic ring or acondensed 5 or 6 membered unsaturated heterocyclic ring containing 1 or2 heteroatom(s) selected from O and S, wherein said phenyl, carbocyclicor heterocyclic ring is unsubstituted or substituted with 1 or 2substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkoxy-(C═O)—;R₁₀ is, independently at each occurrence, H, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)— or R₁₁—(O═S═O)—;R₁₁ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl or mono- or di(C₁-C₆)alkylamino;m is 0, 1 or 2; andn is 1 or 2;or a pharmaceutically acceptable salt or ester thereof;with the provisos that the compound is not1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-[1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-yl)-ethyl]-3,5-dimethyl-piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine,1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine,1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine,1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine,1-[1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-yl)-ethyl]-3,5-dimethyl-piperidine,dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid methylester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-oxo-piperidine-3-carboxylicacid methyl ester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid methyl ester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid methyl ester,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolineor1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl-3-(3-trifluoromethyl-phenyl)-pyrrolidine.

In a possible subgroup of the compounds of formula I, Z is—[C(R₄)₂]_(n)—.

In a further possible subgroup of the compounds of formula I, n is 1.

In another possible subgroup of the compounds of formula I, n is 2.

In a further possible subgroup of the compounds of formula I, Z is asingle bond.

In a further possible subgroup of the compounds of formula I, R₂ is H.

In a further possible subgroup of the compounds of formula I, R₃ is H.

In a further possible subgroup of the compounds of formula I, R₄ is,independently at each occurrence, H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₂-C₆)alkenyloxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkoxy-(C═O)—, hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl; for example, H.

In another possible subgroup of the compounds of formula I, R₄ is,independently at each occurrence, H, hydroxy or (C₁-C₆)alkyl; forexample, H.

In a further possible subgroup of the compounds of formula I, m is 0.

In another possible subgroup of the compounds of formula I, m is 1.

In a further possible subgroup of the compounds of formula I, R₁ is,independently at each occurrence, hydroxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C═O)—, CN, NO₂, NH₂, mono- or di(C₁-C₆)alkylamino orcarboxy.

In a further possible subgroup of the compounds of formula I, R₁ is,independently at each occurrence, hydroxy, halogen, phenyl(C₁-C₆)alkoxyor NO₂.

In another possible subgroup of the compounds of formula I, R₁ is,independently at each occurrence, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxyor halogen; for example, hydroxy or halogen.

In a further possible subgroup of the compounds of formula I, X isC(R₅)(R₆).

In a further possible subgroup of the compounds of formula I, R₅ is H.

In another possible subgroup of the compounds of formula I, R₅ ishydroxy.

In another possible subgroup of the compounds of formula I, R₄ and R₅attached to adjacent carbon ring atoms form a bond between the carbonring atoms to which they are attached.

In a further possible subgroup of the compounds of formula I, R₆ isunsubstitued phenyl.

In another possible subgroup of the compounds of formula I,

R₆ is phenyl substituted with 1 or 2 substituent(s) R₉;R₉ is, independently at each occurrence, hydroxy, (C₂-C₆)alkenyl,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl,hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₂-C₆)alkenyloxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy, hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—N(R₁₀)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, NO₂, (R₁₀)₂N—, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)—,(R₁₀)₂N—(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl, carboxy, R₁₁—(O═S═O)—or R₁₁—(O═S═O)—O—;or R₉ and R₉ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed phenylring, a condensed 5 or 6 membered unsaturated carbocyclic ring or acondensed 5 or 6 membered unsaturated heterocyclic ring containing 1 or2 heteroatom(s) selected from O and S, wherein said phenyl, carbocyclicor heterocyclic ring is unsubstituted or substituted with 1 or 2substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkoxy-(C═O)—.

In another possible subgroup of the compounds of formula I,

R₆ is phenyl substituted with 1 or 2 substituent(s) R₉;R₉ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,hydroxy-(C═O)—(C₁-C₆)alkoxy, CN, (R₁₀)₂N—, (R₁₀)₂N—(C═O)—, R₁₁—(O═S═O)—or R₁₁—(O═S═O)—O—;or R₉ and R₉ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed 5 memberedunsaturated heterocyclic ring containing 2 heteroatoms selected from O,wherein said heterocyclic ring is unsubstituted; for example, R₆ isphenyl substituted with 1 substituent R₉ and R₉ is hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkoxy or (R₁₀)₂N—.

In another possible subgroup of the compounds of formula I, X isC(R₇)(R₈).

In a further possible subgroup of the compounds of formula I, R₇ is H,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl or (C₁-C₆)alkoxy-(C═O)—;for example, H.

In a further possible subgroup of the compounds of formula I, R₇ is(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy-(C═O)—; for example, (C₁-C₆)alkyl.

In another possible subgroup of the compounds of formula I, R₄ and R₇attached to adjacent carbon ring atoms form a bond between the carbonring atoms to which they are attached.

In a further possible subgroup of the compounds of formula I, R₈ is(C₂-C₆)alkenyl, halogen, halo(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl,hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₂-C₆)alkenyloxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,hydroxy-(C═O)—(C₁-C₆)alkoxy, hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)allyl-(O═S═O)—O—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—N(R₁₀)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, NO₂, (R₁₀)₂N—, (R₁₀)₂N—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl, R₁₁—(O═S═O)— orR₁₁—(O═S═O)—O—; for example, (C₂-C₆)alkenyl, halogen,hydroxy(C₂-C₆)alkenyl, hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₂-C₆)alkenyloxy(C₁-C₆)alkyl, hydroxy-(C═O)—(C₁-C₆)alkoxy,hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-S—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-O—(O═S═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—N(R₁₀)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, CN, NO₂,(R₁₀)₂N—(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(R₁₀)₂N—(C═O)—(C₁-C₆)alkyl-(O═S═O)—(C₁-C₆)alkyl or R₁₁—(O═S═O)—O—.

In another possible subgroup of the compounds of formula I, R₈ ishydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, halogen, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₂-C₆)alkenyloxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkoxy-(C═O)—, (C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)— or carboxy; for example,hydroxy, (C₂-C₆)alkenyl, halogen, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₂-C₆)alkenyloxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)— or carboxy; such ashydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl orhydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl.

In another possible subgroup of the compounds of formula I, R₄ and R₈attached to adjacent carbon ring atoms form, together with the carbonring atoms to which they are attached, a condensed phenyl ring, whereinsaid phenyl ring is unsubstituted or substituted with 1 or 2substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkoxy-(C═O)—;for example, R₄ and R₈ attached to adjacent carbon ring atoms form,together with the carbon ring atoms to which they are attached, acondensed phenyl ring, wherein said phenyl ring is substituted with 1substituent being hydroxy(C₁-C₆)alkyl or (C₁-C₆)alkoxy-(C═O)—.

In another possible subgroup of the compounds of formula I, R₄ and R₈attached to adjacent carbon ring atoms form, together with the carbonring atoms to which they are attached, a condensed 5 or 6 memberedsaturated or unsaturated carbocyclic ring or a condensed 5 or 6 memberedsaturated or unsaturated heterocyclic ring containing 1 or 2heteroatom(s) selected from N, O, and S, wherein said carbocyclic orheterocyclic ring is unsubstituted or substituted with 1 or 2substituent(s) each independently being hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)— oroxo.

In yet another possible subgroup of the compounds of formula I, R₄ andR₈ attached to adjacent carbon ring atoms form, together with the carbonring atoms to which they are attached, a condensed 6 membered saturatedcarbocyclic ring, wherein said carbocyclic ring is unsubstituted.

In yet another possible subgroup of the compounds of formula I, R₄ andR₈ attached to adjacent carbon ring atoms form, together with the carbonring atoms to which they are attached, a condensed 5 or 6 memberedsaturated or unsaturated heterocyclic ring containing 1 or 2heteroatom(s) selected from N, O, and S, wherein said heterocyclic ringis unsubstituted or substituted with 1 or 2 substituent(s) eachindependently being hydroxy, (C₁-C₆)allyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)— or oxo.

In another possible subgroup of the compounds of formula I, R₇ and R₈form, together with the carbon ring atom to which they are attached, a 5or 6 membered saturated carbocyclic ring or a 5 or 6 membered saturatedheterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O,and S, wherein said carbocyclic or heterocyclic ring is unsubstituted orsubstituted with 1 or 2 substituent(s) each independently being hydroxy,(C₁-C₆)alkyl or oxo; for example, R₇ and R₈ form, together with thecarbon ring atom to which they are attached, a 5 or 6 membered saturatedheterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O,and S, wherein said heterocyclic ring is unsubstituted or substitutedwith 1 or 2 substituent(s) each independently being hydroxy,(C₁-C₆)alkyl or oxo.

In a further possible subgroup of the compounds of formula I, X isC(R₅)(R₆) or C(R₇)(R₈);

Z is —[C(R₄)₂]_(n)— or a single bond;R₁ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, phenyl(C₁-C₆)alkoxy or NO₂;R₂ is, independently at each occurrence, H;R₃ is, independently at each occurrence, H;R₄ is, independently at each occurrence, H, hydroxy or (C₁-C₆)alkyl;or R₄ and R₄ both attached to the same carbon ring atom form, togetherwith the carbon ring atom to which they are attached, a —(C═O)— group;

R₅ is H;

or R₄ and R₅ attached to adjacent carbon ring atoms form a bond betweenthe carbon ring atoms to which they are attached;R₆ is phenyl unsubstituted or substituted with 1 or 2 substituent(s) R₉;R₇ is H, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy-(C═O)—;or R₄ and R₅ attached to adjacent carbon ring atoms form a bond betweenthe carbon ring atoms to which they are attached;R₈ is hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy, halogen,hydroxy(C₁-C₆)allyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₂-C₆)alkenyloxy(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkoxy-(C═O)—,(C₁-C₆)alkoxy-(C₁-C₆)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl,hydroxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C═O)—(C₁-C₆)alkoxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl-S—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(O═S═O)—O—(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo (C₁-C₆)alkoxy(C₁-C₆)alkyl,CN, (R₁₀)₂N—(C₁-C₆)alkyl, (R₁₀)₂N—(C═O)—, carboxy, or(C₁-C₆)alkoxy-(C₁-C₆)alkoxy;or R₄ and R₈ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed phenylring, wherein said phenyl ring is unsubstituted or substituted with 1 or2 substituent(s) each independently being hydroxy(C₁-C₆)alkyl or(C₁-C₆)alkoxy-(C═O)—;or R₄ and R₈ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed 6 memberedsaturated carbocyclic ring, wherein said carbocyclic ring isunsubstituted;R₉ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,hydroxy-(C═O)—(C₁-C₆)alkoxy, CN, (R₁₀)₂N—, (R₁₀)₂N—(C═O)—, R₁₁—(O═S═O)—or R₁₁—(O═S═O)—O—;or R₉ and R₉ attached to adjacent carbon ring atoms form, together withthe carbon ring atoms to which they are attached, a condensed 5 or 6membered unsaturated heterocyclic ring containing 1 or 2 heteroatom(s)selected from O, wherein said phenyl, carbocyclic or heterocyclic ringis unsubstituted;R₁₀ is, independently at each occurrence, H or (C₁-C₆)alkyl,R₁₁ is, independently at each occurrence, (C₁-C₆)alkyl orhalo(C₁-C₆)alkyl;m is 0, 1 or 2; andn is 1 or 2.

In another possible subgroup of the compounds of formula I, X isC(R₅)(R₆) or C(R₇)(R₈);

Z is —[C(R₄)₂]_(n)—;R₁ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl, orhalogen;R₂ is, independently at each occurrence, H;R₃ is, independently at each occurrence, H;R₄ is, independently at each occurrence, H;

R₅ is H;

R₆ is phenyl unsubstituted or substituted with 1 or 2 substituent(s) R₉;R₇ is (C₁-C₆)alkyl;R₈ is hydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,R₉ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkoxy or (R₁₀)₂N—;R₁₀ is, independently at each occurrence, H or (C₁-C₆)alkyl,m is 0 or 1;n is 1.In yet another possible subgroup of the compounds of formula I,

X is C(R₅)(R₆) or C(R₇)(R₈);

Z is a single bond;R₁ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl, orhalogen;R₂ is, independently at each occurrence, H;R₃ is, independently at each occurrence, H;R₄ is, independently at each occurrence, H;

R₅ is H;

R₆ is phenyl unsubstituted or substituted with 1 or 2 substituent(s) R₉;R₇ is H or (C₁-C₆)alkyl;R₈ is hydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkoxy(C₁-C₆)alkyl,R₉ is, independently at each occurrence, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halogen, hydroxy(C₁-C₆)alkoxy or (R₁₀)₂N—;R₁₀ is, independently at each occurrence, H or (C₁-C₆)alkyl,m is 0 or 1;n is 1.

In a further possible subgroup of the compounds of formula I, thecompound is1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-phenyl-1,2,3,6-tetrahydropyridine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-phenylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyphenyl)piperidine,3-(4-chlorophenyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-methoxyphenyl)piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-p-tolylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(4-methoxyphenyl)piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-o-tolylpiperidine,4-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-fluorophenyl)piperidine,3-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol,2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl]-3-(2-fluorophenyl)piperidine,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-fluorophenyl)piperidine.HCl,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-trifluoromethyl-phenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine,(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine.HCl,(S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine,(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol,(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol.HCl,(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol,acetic acid3-{(S)-1-[(R*)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenylester.HCl,2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanol,3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-ol,trifluoromethanesulfonic acid3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenylester,(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)aceticacid,3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-benzonitrile,3-benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine,3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol,(S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol,3-[(R*)-1-((S)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol,(S)-3-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol,3-[(R*)-1-((S)-8-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol,(S)-3-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-5-ol,(R*)-3-[1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-methyl-1,2,3,6-tetrahydropyridine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-1,2,3,6-tetrahydropyridine,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,5,6-tetrahydropyridin-3-yl]methanol,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)decahydroisoquinoline,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidethyl ester,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylicacid ethyl ester,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethyl-3-methylpiperidine,3-chloromethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine,2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(1-methoxy-1-methylethyl)-3-methylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-hydroxymethyl-3-methylpiperidin-4-ol,acetic acid1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester, methanesulfonic acid1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethoxymethyl-3-methylpiperidine,1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone,1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanol,3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine,2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol,3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine,3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylicacid ethyl ester,[3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol,3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethylpiperidine,3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethylpiperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluoroethoxymethyl)-piperidine,2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethoxy]ethanol,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]acetic acidethyl ester,2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyethyl)piperidine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidamide,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carbonitrile,C-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methylamine,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-ol,2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline-8-carboxylicacid methyl ester,[2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]methanol,(5)-1-((R)-2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylicacid ethyl ester, lithium(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylate,{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol,2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol,2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanolD-tartrate,(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidine,(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-(2,2,2-trifluoroethoxymethyl)piperidine,methanesulfonic acid(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethylester, thioacetic acidS-{(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl}ester,2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl-sulfanyl}ethanol,{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}aceticacid tert-butyl ester, sodium{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl-methoxy}acetate,2-[(S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol,1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylicacid ethyl ester,[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidin-3-yl]methanol,(5)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylicacid ethyl ester,[(S)-1-((S)-7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol,(S)-1-((S)-7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine,(S)-1-((S)-7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine.HCl,(5)-1-[(S)-1-(2,3-dihydro-benzo[1,4]-dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidine,3-{(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenylamine,(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoloxalate,(S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol,1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine,(5)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-fluoro-ethoxymethyl)-3-methyl-piperidine.HCl,(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(3-fluoromethoxy-phenyl)-piperidine,1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylicacid methyl ester,[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-yl]-methanol,2-[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-ylmethoxy]-ethanol,1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylicacid methyl ester,[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanol,2-[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-ylmethoxy]-ethanol,1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-pyrrolidineor3-[(R)-1-((S)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol.

It is evident to a person skilled in the art that, in the compounds offormula I, when the substituents R₉ and R₉ attached to adjacent carbonring atoms form, together with the carbon ring atoms to which they areattached, a condensed 5 or 6 membered unsaturated carbocyclic ring or acondensed 5 or 6 membered unsaturated heterocyclic ring, saidcarbocyclic ring or heterocyclic ring may have further unsaturated bondsin addition to the unsaturated bond between the carbon ring atoms, towhich said substituents are attached.

The terms employed herein have the meanings indicated below. The term“at least one” employed in the meanings below refers to one or several,such as one. For example, the term “at least one halogen” refers to oneor several halogens, such as one halogen.

The term “hydroxy”, as employed herein as such or as part of anothergroup, refers to a —OH group.

The term “(C₁-C₆)alkyl”, as employed herein as such or as part ofanother group, refers to a straight or branched chain saturatedhydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atom(s).Representative examples of (C₁-C₆)alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, and n-hexyl.

The term “(C₁-C₆)alkoxy”, as employed herein as such or as part ofanother group, refers to an (C₁-C₆)alkyl group, as defined herein,appended to the parent molecular moiety through an oxygen atom.Representative examples of (C₁-C₆)alkoxy include, but are not limitedto, methoxy, ethoxy, n-propoxy, n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy, 2,2-dimethylpropoxy, 3-methylbutoxy, and n-hexoxy.

The term “halo” or “halogen”, as employed herein as such or as part ofanother group, refers to fluorine, chlorine, bromine or iodine.

The term “halo(C₁-C₆)alkyl”, as employed herein, refers to at least onehalogen, as defined herein, appended to the parent molecular moietythrough an (C₁-C₆)alkyl group, as defined herein. When there are severalhalogens, the halogens can be identical or different. Representativeexamples of halo(C₁-C₆)alkyl include, but are not limited to,fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,2-chloroethyl, 3-bromopropyl, and 2-chloropropyl.

The term “phenyl(C₁-C₆)alkoxy”, as employed herein, refers to at leastone phenyl group appended to the parent molecular moiety through an(C₁-C₆)alkoxy group, as defined herein. Representative examples ofphenyl(C₁-C₆)alkoxy include, but are not limited to, phenylmethoxy,2-phenylethoxy, and 3-phenylpropoxy.

The term “amino”, as employed herein as part of another group, refers toa —NH₂ group.

The term “mono(C₁-C₆)alkylamino”, as employed herein, refers to one(C₁-C₆)alkyl group, as defined herein, appended to the parent molecularmoiety through an amino group, as defined herein. Representativeexamples of mono(C₁-C₆)alkylamino include, but are not limited to,N-methylamino, N-ethylamino, and N-butylamino.

The term “di(C₁-C₆)alkylamino”, as employed herein, refers to two(C₁-C₆)alkyl groups, as defined herein, appended to the parent molecularmoiety through an amino group, as defined herein. The (C₁-C₆)alkylgroups can be identical or different. Representative examples ofdi(C₁-C₆)alkylamino include, but are not limited to, N,N-dimethylaminoand N,N-diethylamino.

The term “carboxy”, as employed herein, refers to a —COOH group.

The term “(C₂-C₆)alkenyl”, as employed herein as such or as part ofanother group, refers to a straight or branched chain hydrocarbon grouphaving 2, 3, 4, 5 or 6 carbon atoms and containing at least onecarbon-carbon double bond. Representative examples of (C₂-C₆)alkenylinclude, but are not limited to, ethenyl and prop-2-enyl.

The term “hydroxy(C₁-C₆)alkyl”, as employed herein as such or as part ofanother group, refers to at least one hydroxy group, as defined herein,appended to the parent molecular moiety through an (C₁-C₆)alkyl group,as defined herein. Representative examples of hydroxy(C₁-C₆)alkylinclude, but are not limited to, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2,2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl,1-hydroxy-1-methylethyl, and 1-hydroxy-1-methylpropyl.

The term “hydroxy(C₂-C₆)alkenyl”, as employed herein, refers to at leastone hydroxy group, as defined herein, appended to the parent molecularmoiety through an (C₂-C₆)alkenyl group, as defined herein.Representative examples of hydroxy(C₂-C₆)alkenyl include, but are notlimited to, 1-hydroxyethenyl, 2-hydroxyethenyl, and1-hydroxyprop-2-enyl.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkyl”, as employed herein as such or aspart of another group, refers to at least one (C₁-C₆)alkoxy group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkyl group, as defined herein. When there are several(C₁-C₆)alkoxy groups, the (C₁-C₆)alkoxy groups can be identical ordifferent. Representative examples of (C₁-C₆)alkoxy(C₁-C₆)alkyl include,but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl,2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl,1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl, and 4-methoxybutyl.

The term “(C₂-C₆)alkenyloxy”, as employed herein as part of anothergroup, refers to an (C₂-C₆)alkenyl group, as defined herein, appended tothe parent molecular moiety through an oxygen atom. Representativeexamples of (C₂-C₆)alkenyloxy include, but are not limited to,ethenyloxy, prop-2-enyloxy, bute-2-nyloxy, and hex-3-enyloxy.

The term “(C₂-C₆)alkenyloxy(C₁-C₆)alkyl”, as employed herein, refers toat least one (C₂-C₆)alkenyloxy group, as defined herein, appended to theparent molecular moiety through an (C₁-C₆)alkyl group, as definedherein. When there are several (C₂-C₆)alkenyloxy groups, the(C₂-C₆)alkenyloxy groups can be identical or different. Representativeexamples of (C₂-C₆)alkenyloxy(C₁-C₆)alkyl include, but are not limitedto, prop-2-enyloxymethyl and ethenyloxyethyl.

The term “hydroxy(C₁-C₆)alkoxy”, as employed herein as such or as partof another group, refers to at least one hydroxy group, as definedherein, appended to the parent molecular moiety through an (C₁-C₆)alkoxygroup, as defined herein. Representative examples ofhydroxy(C₁-C₆)alkoxy include, but are not limited to, hydroxymethoxy,dihydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy,2-hydroxybutoxy, and 2-hydroxy-1-methylethoxy.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkoxy”, as employed herein as such or aspart of another group, refers to at least one (C₁-C₆)alkoxy group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkoxy group, as defined herein. The (C₁-C₆)alkoxy groups can beidentical or different. Representative examples of(C₁-C₆)alkoxy(C₁-C₆)alkoxy include, but are not limited to,methoxymethoxy, propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,2-butoxyethoxy, 2,2-dimethoxyethoxy, 1-methyl-2-propoxyethoxy,2-methoxypropoxy and 4-methoxybutoxy.

The term “halo(C₁-C₆)alkoxy”, as employed herein as such or as part ofanother group, refers to at least one halogen, as defined herein,appended to the parent molecular moiety through an (C₁-C₆)alkoxy group,as defined herein. When there are several halogens, the halogens can beidentical or different. Representative examples of halo(C₁-C₆)alkoxyinclude, but are not limited to, fluoromethoxy, chloromethoxy,difluoromethoxy, trifluoromethoxy, 2-bromoethoxy, 2,2,2-trichloroethoxy,3-bromopropoxy, 2-chloropropoxy, and 4-chlorobutoxy.

The term “oxo”, as employed herein, refers to a ═O group.

The expression “compounds of the invention” as employed herein refers tothe compounds of formula I.

Pharmaceutically acceptable salts, e.g. metal salts and acid additionsalts, with both organic and inorganic acids, are known in the field ofpharmaceuticals. Representative examples of pharmaceutically acceptablemetal salts include, but are not limited to, lithium, sodium, potassium,calcium, magnesium, aluminum and zinc salts. Representative examples ofpharmaceutically acceptable acid addition salts include, but are notlimited to, chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, methane sulfonates, formates, tartrates, maleates, citrates,benzoates, salkylates, ascorbates, acetates and oxalates.

Pharmaceutically acceptable esters, when applicable, may be prepared byknown methods using pharmaceutically acceptable acids that areconventional in the field of pharmaceuticals and that retain thepharmacological properties of the free form. Non-limiting examples ofthese esters include esters of aliphatic or aromatic alcohols.Representative examples of pharmaceutically acceptable esters include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, and benzyl esters.

The invention includes within its scope all the possible geometricisomers, e.g. Z and E isomers (cis and trans isomers), of the compoundsas well as all the possible optical isomers, e.g. diastereomers andenantiomers, of the compounds. Furthermore, the invention includes inits scope both the individual isomers and any mixtures thereof, e.g.racemic mixtures. The individual isomers may be obtained using thecorresponding isomeric forms of the starting material or they may beseparated after the preparation of the end compound according toconventional separation methods. For the separation of optical isomers,e.g. enantiomers, from the mixture thereof, conventional resolutionmethods, e.g. fractional crystallization, may be used.

The compounds of formula I can be prepared by a variety of syntheticroutes analogously to or according to methods known in the literatureusing suitable starting materials. The starting materials depicted belowin formulae A, B, C, and D are commercially available or can be preparedvia synthetic routes known in the literature.

Suitable starting materials containing the benzodioxane moiety arecompounds of formulae A and B:

wherein R₁ and m are as defined above and L is a leaving group, e.g.halogen, mesylate or tosylate.

2,3-Dihydrobenzo[1,4]dioxine-2-carboxylic acid (formula A) iscommercially available and easily resolvable to its enantiomers asdescribed in Tetrahedron: Asymmetry, 16 (2005) 1639. Compounds offormula B can be prepared according to known methods.

Suitable starting materials containing the azacycle moiety are suitablysubstituted piperidines or homopiperidines and also, in some cases,pyridines. Such compounds are compounds of formulae C, D, and E:

wherein X and Z are as defined above, R represents R₆ or R₈ as definedabove, and R′ and R″ represent alkyl groups. Although not shown in theirformulae, the heterocyclic rings in compounds of formulae C, D, and Ecan contain further suitable substituents. Compounds of formula E havingtwo substituents attached to the same carbon atom can be prepared, forexample, via a-alkylation of suitable piperidine carboxylates asdescribed in Org. Lett., 7 (2005) 55 or via construction of thepiperidine ring from a proper open chain precursor, e.g. reduction ofsuitably alkylated 2-cyanoacetates. The ester group in compounds offormula E is further transformable to a wide variety of other functionalgroups.

In general, compounds of formula I can be prepared analogously oraccording to scheme 1, wherein X and Z are as defined above:

Another route for preparing amide intermediates of scheme 1, wherein Zis a single bond, proceeds via reaction of a suitable amine and asuitable iteconate analog as described in J. Org. Chem., 26 (1961)1519-1524.

A further route for preparing compounds of formula I is shown in scheme2, wherein X, Z, R₁, and m are as defined above:

Compounds of formula I, wherein R₅ or R₇ is H, can be prepared viaN-alkylation of suitably substituted pyridines followed by reduction asillustrated in scheme 3, wherein R₁, m, L, and R are as defined above:

Resolution of the compounds of formula I that are racemic can be carriedout, if desired, for example, by converting the racemic compound intoits diastereomeric salt mixture by reaction with an optically activeacid and subsequent separation of the diastereomers by crystallization.Representative examples of said optically active acids include, but arenot limited to, D-tartaric acid and dibenzoyl-D-tartaric acid.

A person skilled in the art realizes that any starting material orintermediate in the reactions described above can be protected, ifnecessary, in a manner known in the art. Any protected functionality cansubsequently be deprotected in a manner known in the art.

The synthetic routes described above are meant to illustrate thepreparation of the compounds of formula I and the preparation is by nomeans limited thereto, i.e. there are also other possible syntheticmethods which are within the general knowledge of a person skilled inthe art.

The compounds of formula I may be converted, if desired, into theirpharmaceutically acceptable salt or ester form using methods known inthe art.

The present invention will be explained in more detail by the followingexamples. The examples are meant for illustrating purposes only and donot limit the scope of the invention defined in the claims.

Abbreviations: DCM=dichloromethane, DIPEA=N,N-diisopropylethylamine,DMF=N,N-dimethylformamide, EtOAc=ethyl acetate, IPA=isopropanol,LC-MS=liquid chromatography-mass spectrometry, RT=room temperature,THF=tetrahydrofuran, TLC=thin layer chromatography.

Column chromatography was performed on Silica gel 60 obtained fromMerck, or using a CombiFlash instrument together with Redisep columns,both provided by Teledyne ISCO. Microwave heating was performed using anEmrys Optimiser microwave reactor from Personal Chemistry or anInitiator 2.0 microwave reactor from Biotage. The structures of theproducts were confirmed by ¹H NMR. The spectra were measured with aBruker Avance 400 instrument. LC-MS analyses were performed using Waters2690 Alliance HPLC and Waters Micromass ZQ4000 single quadrupole massspectrometer using ESI.

Preparation of Starting Materials

3-(Piperidin-3-yl)phenol HBr can be prepared from3-(3-methoxyphenyl)piperidine as described in J. Med. Chem., 24 (1981)1475.

2-(Piperidin-3-yl)phenol.HBr was prepared by heating3-(2-methoxyphenyl)piperidine.HCl (46 mg, 0.20 mmol) with 48 HBr in amicrowave reactor at 120° C. for one hour. After evaporation, 61 mg ofthe title compound was obtained.

4-(Piperidin-3-yl)phenol.HBr was prepared by heating3-(4-methoxyphenyl)piperidine.HCl (46 mg, 0.20 mmol) with 48% HBr in amicrowave reactor at 120° C. for one hour. After evaporation, 53 mg ofthe title compound was obtained.

(R*)-3-(3-Methoxyphenyl)piperidine was prepared by crystallographicresolution with D-(−)-tartaric acid as described for an analogoussubstrate in Tetrahedron Lett., 35 (1994) 9063.

(R*)-3-(Piperidin-3-yl)phenol.HBr or .HCl was prepared from(R*)-3-(3-methoxyphenyl)piperidine by the method described above for theracemate. Concentrated HCl can be used instead of 48% HBr.

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carboxylic acid was obtained from thecommercially available racemate as described in Tetrahedron: Asymmetry,16 (2005) 1639.

-   (R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride can be prepared    by heating (R)-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid at    70° C. in the presence of excess thionyl chloride for 1-8 h.    Catalytic amount of DMF can be added. Evaporation to dryness gives    the title compound in high yield.

Methanesulfonic acid(R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester was preparedin four steps from 5′-fluoro-2′-hydroxyacetophenone according toanalogous methods described in the literature (J. Med. Chem., 30 (1987)814 and U.S. Pat. No. 5,935,973).

PREPARATION OF INTERMEDIATES Intermediate A1:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(2-fluorophenyl)piperidin-1-yl]methanoneIntermediate A2:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(2-fluorophenyl)piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (46 mg, 0.23 mmol)in DCM (1 ml) was added to a cold solution of3-(2-fluorophenyl)piperidine HCl (50 mg, 0.23 mmol) and DCM (1 ml).Triethylamine (56 mg, 0.55 mmol) was added. The mixture was stirred for50 min. Water (1 ml) was added and the aqueous phase extracted with DCM(3×1 ml). The combined organics were absorbed on silica. The mixture waspurified by flash chromatography using heptane/EtOAc as eluent. Thefirst eluting diastereomer was collected to afford 24 mg of A1(rotameric mixture).

¹H NMR (CDCl₃): δ 1.63-1.73 (m, 1H), 1.79-1.96 (m, 2H), 2.03-2.14 (m,1H), 2.63-2.75 (m, 0.5H), 2.80 (t, 0.5H), 2.98-3.16 (m, 1.5H), 3.20 (t,0.5H), 4.14-4.26 (m, 1H), 4.29-4.38 (m, 1H), 4.48-4.55 (m, 1H),4.67-4.75 (m, 1H), 4.84-4.93 (m, 1H) 6.78-7.06 (m, 7H), 7.26-7.33 (m,1H).

The second eluting diastereomer was collected to afford 25 mg of A2(rotameric mixture).

¹H NMR (CDCl₃): δ 1.60-1.76 (m, 1H), 1.78-1.95 (m, 2H), 2.02-2.13 (m,1H), 2.62-2.71 (m, 0.7H), 2.80 (t, 0.3H), 2.98-3.35 (m, 2H), 4.14-4.25(m, 1H), 4.29-4.39 (m, 1H), 4.45-4.57 (m, 1H), 4.65-4.74 (m, 1H),4.76-4.82 (m, 0.7H), 4.86-4.93 (m, 0.3H), 6.81-7.30 (m, 8H).

Intermediate A3:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluorophenyl)piperidin-1-yl]methanoneIntermediate A4:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-fluorophenyl)piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (46 mg, 0.23 mmol)in DCM (1 ml) was added to a cold solution of3-(3-fluorophenyl)piperidine HCl (50 mg, 0.23 mmol) and DCM (1 ml).Triethylamine (56 mg, 0.55 mmol) was added and the mixture was stirredfor 50 min. After aqueous work-up as described for intermediate A1, thecrude mixture was purified by flash chromatography using heptane/EtOAcas eluent. The first eluting diastereomer was collected to give 29 mg ofA3.

¹H NMR (CDCl₃): δ 1.61-2.00 (m, 2H), 2.06-2.17 (m, 1H), 2.58-2.82 (m,2H), 3.04-3.12 (m, 0.7H), 3.18-3.28 (t, 0.3H), 4.10-4.25 (m, 2H),4.27-4.39 (m, 1H), 4.46-4.54 (m, 1H), 4.65-4.76 (m, 1H), 4.84-4.90 (m,1H) 6.80-7.06 (m, 7H), 7.26-7.33 (m, 1H).

The second eluting diastereomer was collected to afford 19 mg of A4.

¹H NMR (CDCl₃): δ 1.59-1.81 (m, 2H), 1.86-1.96 (m, 1H), 2.08-2.20 (m,1H), 2.61-3.30 (m, 3H), 4.14-4.25 (m, 1H), 4.30-4.41 (m, 1H), 4.48-4.57(m, 1H), 4.65-4.72 (m, 1H), 4.77-4.83 (m, 0.7H), 4.86-4.90 (m, 0.3H),6.80-7.09 (m, 7H), 7.26-7.34 (m, 1H).

Intermediate A5:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-fluorophenyl)piperidin-1-yl]methanoneIntermediate A6:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-fluorophenyl)piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (46 mg, 0.23 mmol)in DCM (1 ml) was added to a cold solution of3-(4-fluorophenyl)piperidine.HCl (50 mg, 0.23 mmol) and DCM (1 ml).Triethylamine (56 mg, 0.55 mmol) was added and the mixture was stirredfor 50 min. After aqueous work-up as described for intermediate A1, thecrude mixture was purified by flash chromatography using heptane/EtOAcas eluent. Again, the first eluting diastereomer was collected to give37 mg of A5.

¹H NMR (CDCl₃): δ 1.60-2.00 (m, 3H), 2.04-2.16 (m, 1H), 2.56-2.81 (m,2H), 3.05-3.15 (m, 0.6H), 3.20 (t, 0.4H), 4.13-4.24 (m, 1H), 4.28-4.40(m, 1H), 4.47-4.55 (m, 1H), 4.65-4.74 (m, 1H), 4.84-4.89 (m, 1H)6.70-6.95 (m, 4H), 6.98-7.05 (m, 2H), 7.15-7.24 (m, 2H).

The second eluting diastereomer was collected to afford 20 mg of A6.

¹H NMR (CDCl₃): δ 1.60-1.76 (m, 1H), 1.78-1.95 (m, 2H), 2.02-2.13 (m,1H), 2.62-2.71 (m, 0.7H), 2.80 (t, 0.3H), 2.98-3.35 (m, 2H), 4.14-4.25(m, 1H), 4.29-4.39 (m, 1H), 4.45-4.57 (m, 1H), 4.65-4.74 (m, 1H),4.76-4.82 (m, 0.7H), 4.86-4.93 (m, 0.3H), 6.81-7.30 (m, 8H).

Intermediate A7:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxyphenyl)piperidin-1-yl]methanoneIntermediate A8:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-hydroxyphenyl)piperidin-1-yl]methanone

A mixture of (R)-2,3 dihydrobenzo[1,4]dioxine-2-carboxylic acid (5.06 g,28.1 mmol), toluene (25 ml) and thionyl chloride (6.68 ml, 56.2 mmol)was heated to reflux. After 1.5 hours the reaction mixture was cooleddown and evaporated to dryness. Toluene was added to the evaporationresidue and evaporated to dryness. The evaporation residue in THF (10ml) was added slowly to a mixture of (R*)-3-(piperidin-3-yl)phenolhydrochloride (5.0 g, 23.4 mmol), potassium carbonate (4.85 g, 35.1mmol), water (16.5 ml) and THF (33.5 ml). After the addition thereaction mixture was stirred at RT for 10 minutes, layers were separatedand organic phase was washed with aq NaCl solution. The organic phasewas evaporated to dryness and the evaporation residue was crystallizedfrom ethyl acetate to yield 6.79 g of A7.

¹H NMR (CDCl₃): δ 1.60-1.97 (m, 3H), 2.05-2.15 (m, 1H), 2.62-2.76 (m,2H), 3.05-3.27 (m, 1H), 4.15-4.18 (m, 1H), 4.31-4.37 (m, 1H), 4.48-4.52(m, 1H), 4.66-4.68 (m, 1H), 4.86-4.89 (m, 1H), 5.25 & 5.40 (2×s, 1H),6.71-6.94 (m, 7H), 7.16-7.20 (m, 1H).

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (475 mg, 2.4 mmol)in DCM (4 ml) was added to a mixture of 3-(piperidin-3-yl)phenol HBr(259 mg, 1.06 mmol), triethylamine (307 mg, 3.01 mmol) and DCM (4 ml).The mixture was stirred for 2 h, after which 1 M HCl (5 ml) was added.The phases were separated and the organic phase was absorbed on silica.The mixture was purified by flash chromatography using heptane/EtOAc aseluent. The fractions containing the second eluting diastereomer werecollected. The isolated product (199 mg) was the compound which had beenacylated on both the amine and the phenol. The ester bond was hydrolysedby treating the compound with two equivalents of KOH in MeOH (5 ml) forone hour. The mixture was evaporated to dryness, the crude product wastaken up in EtOAc (10 ml), washed with 1 M K₂CO₃, dried and evaporatedto dryness to afford 77 mg of A8.

¹H NMR (CDCl₃): δ 1.59-1.95 (m, 3H), 2.06-2.15 (m, 1H), 2.61-3.30 (m,3H), 4.13-4.23 (m, 1H), 4.31-4.39 (m, 1H), 4.46-4.55 (m, 1H), 4.65-4.71(m, 1H), 4.80-4.92 (m, 2H), 6.65-6.98 (m, 7H), 7.15-7.28 (m, 1H).

Intermediate A9:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]-methanoneIntermediate A10:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-trifluoromethylphenyl)-piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (44 mg, 0.22 mmol)in DCM (1 ml) was added to a mixture of3-(3-trifluoromethylphenyl)piperidine HCl (50 mg, 0.19 mmol) and DCM (1ml). Triethylamine (54 mg, 0.53 mmol) was added and the mixture wasstirred for 1 h. 1 M HCl (2 ml) was added, and the phases wereseparated. The organic phase was absorbed on silica and the crudemixture was purified by flash chromatography using heptane/EtOAc aseluent. The fractions containing the first eluting diastereomer werecollected to give 30 mg of A9.

¹H NMR (CDCl₃): δ 1.72-2.00 (m, 3H), 2.06-2.20 (m, 1H), 2.60-2.87 (m,2H), 3.06-3.16 (m, 0.7H), 3.26 (t, 0.3H), 4.16-4.26 (m, 1H), 4.27-4.40(m, 1H), 4.46-4.55 (m, 1H), 4.67-4.80 (m, 1H), 4.84-4.91 (m, 1H)6.79-6.95 (m, 4H), 7.40-7.56 (m, 4H).

The second eluting diastereomer was collected to afford 19 mg of A10.

¹H NMR (CDCl₃): δ 1.59-1.99 (m, 3H), 2.08-2.19 (m, 1H), 2.61-3.34 (m,3H), 4.14-4.25 (m, 1H), 4.30-4.41 (m, 1H), 4.48-4.57 (m, 1H), 4.65-4.72(m, 1H), 4.77-4.83 (m, 0.7H), 4.86-4.90 (m, 0.3H), 6.80-7.09 (m, 7H),7.26-7.34 (m, 1H).

Intermediate A11:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]-methanoneIntermediate A12:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-trifluoromethylphenyl)-piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (44 mg, 0.22 mmol)was dissolved in DCM (4 ml). 3-(4-Trifluoromethylphenyl)piperidine HCl(51 mg, 0.19 mmol) and triethylamine were added. The mixture was stirredfor 1 h, 1 M HCl (2 ml) was added, and the phases were separated. Theorganic phase was absorbed on silica and the mixture purified by flashchromatography using heptane/EtOAc as eluent. The fractions containingthe first eluting diastereomer were collected to yield 21 mg of All.

¹H NMR (CDCl₃): δ 1.64-2.01 (m, 3H), 2.07-2.18 (m, 1H), 2.62-2.75 (m,1H), 2.77-2.88 (m, 1H), 3.07-3.18 (m, 0.6H), 3.26 (t, 0.4H), 4.16-4.27(m, 1H), 4.26-4.40 (m, 1H), 4.47-4.58 (m, 1H), 4.67-4.77 (m, 1H),4.84-4.91 (m, 1H) 6.77-6.99 (m, 4H), 7.32-7.42 (m, 2H), 7.55-7.65 (m,2H).

The second eluting diastereomer was collected to afford 21 mg of A12.

¹H NMR (CDCl₃): δ 1.59-1.97 (m, 3H), 2.06-2.19 (m, 1H), 2.59-3.36 (m,3H), 4.16-4.26 (m, 1H), 4.33-4.40 (m, 1H), 4.46-4.55 (m, 1H), 4.65-4.75(m, 1H), 4.78-4.83 (m, 0.7H), 4.86-4.93 (m, 0.3H), 6.82-6.94 (m, 4H),7.27-7.46 (m, 2H), 7.54-7.64 (m, 2H).

Intermediate A13:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-methoxyphenyl)piperidin-1-yl]methanoneIntermediate A14:(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-methoxyphenyl)piperidin-1-yl]methanone

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (3.04 g, 15.3 mmol)was dissolved in DCM (50 ml). (R*)-3-(3-Methoxyphenyl)piperidine (2.92g, 15.3 mmol) and triethylamine (1.87 g, 18.36 mmol) were added. Afterstirring for 40 min, the mixture was washed with water (50 ml), 1 MNa₂CO₃ (50 ml) and 1 M HCl (50 ml). Drying (Na₂SO₄) and evaporation gave5.12 g of A13.

¹H NMR (CDCl₃): δ 1.58-1.99 (m, 3H), 2.06-2.17 (m, 1H), 2.58-2.82 (m,2H), 3.05-3.17 (m, 0.6H), 3.20-3.29 (m, 0.4H), 3.80 (s, 3H), 4.15-4.23(m, 1H), 4.27-4.39 (m, 1H), 4.48-4.52 (m, 1H), 4.65-4.77 (m, 1H),4.84-4.90 (m, 1H) 6.71-6.96 (m, 7H), 7.23-7.30 (m, 1H).

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (54 mg, 0.27 mmol)was dissolved in DCM (4 ml). 3-(3-Methoxyphenyl)piperidine HCl (72 mg,0.26 mmol) and triethylamine (59 mg, 0.58 mmol) were added. Afterstirring for 1 h, acidic work-up as above gave the crude product, whichwas purified by flash chromatography using heptane/EtOAc as eluent. Thesecond eluting diastereomer was collected to give 19 mg of A14.

¹H NMR (CDCl₃): δ 1.57-1.99 (m, 3H), 2.08-2.21 (m, 1H), 2.60-3.31 (m,3H), 3.81 (s, 3H), 4.17-4.25 (m, 1H), 4.31-4.40 (m, 1H), 4.45-4.55 (m,1H), 4.66-4.75 (m, 1H), 4.77-4.85 (m, 0.7H), 4.86-4.90 (m, 0.3H),6.78-7.01 (m, 7H), 7.23-7.33 (m, 1H).

Reduction of Intermediates: General Procedure

The intermediate (A1-A14) was dissolved in dry THF (c=0.1-0.5 M). BH₃THF (1 M in THF, 5-7 equivalents) was added and the mixture stirred at60-90° C. using microwave heating or an oil bath (reaction times from 20min up to 16 h). The formation of amine-borane-complexes was monitoredby TLC or LC-MS. To the ice bath cooled mixture 1 M HCl was added inlarge excess, and the mixture was stirred at 40-60° C. for 20 min-12 h.The progress of the hydrolysis of the borane-complexes was monitored byTLC or LC-MS. The mixture was placed on an ice-bath, and solid KOH orNa₂CO₃ was added until the mixture was alkaline. THF was removed byevaporation before or after addition of base. The remaining aqueousphase was extracted with EtOAc or DCM. The organics were pooled, dried(Na₂SO₄) and evaporated to dryness. The crude product was purified bycolumn chromatography, using a gradient of EtOAc/heptane, with orwithout 1% triethylamine added, or by crystallisation from a suitablesolvent.

Preparation of Compounds of the Invention Example 11-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-phenyl-1,2,3,6-tetrahydropyridine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18mmol) and 3-phenyl-pyridine (339 mg, 2.18 mmol) in xylene (2 ml) wasrefluxed for 4 h. After cooling, the solvent was decanted to give thecrude oily pyridinium salt, which was dissolved in MeOH (5 ml). NaBH₄(330 mg, 4 eq) was added in small portions to the cooled mixture. Afterstirring for 2 h at RT, MeOH was evaporated, water was added and themixture extracted with EtOAc. Drying (Na₂SO₄) and evaporation gave thecrude product, which was purified by flash chromatography(heptane/EtOAc).

¹H NMR (CDCl₃): δ 2.36 (m, 1H), 2.66-2.92 (m, 4H), 3.40-3.55 (m, 2H),4.04 (m, 1H), 4.30-4.45 (m, 2H), 6.13 (m, 1H), 6.80-6.95 (m, 4H),7.20-7.35 (m, 5H).

Example 2 1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-phenylpiperidine

The procedure above was repeated except that the crude pyridium salt washydrogenated in MeOH under normal pressure (6.5 h, RT) using PtO₂ ascatalyst. After alkaline work-up the crude product was purified by flashchromatography (heptane/EtOAc).

¹H NMR (CDCl₃): δ 1.40-1.51 (m, 1H), 1.60-1.85 (m, 2H), 2.11 (br d, 1H),2.05-2.28 (m, 2H), 2.58 (ddd, 1H), 2.66-2.75 (m, 1H), 2.78-3.10 (m, 3H),3.92-4.05 (m, 1H), 4.25-4.37 (m, 2H), 6.77-6.90 (m, 4H), 7.15-7.32 (m,5H).

Example 31-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyphenyl)piperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15mmol), 3-(2-methoxyphenyl)piperidine HCl (38 mg, 0.165 mmol) andtriethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in amicrowave reactor at 110-150° C. for 90 min. After evaporation todryness, the crude product was purified by flash chromatography using agradient of heptane and EtOAc as eluent to give 12 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.40-1.53 (m, 1H), 1.71-1.81 (m, 2H), 1.82-1.90 (m,1H), 2.06-2.18 (m, 2H), 2.54-2.65 (m, 1H), 2.67-2.75 (m, 1H), 2.90-3.02(m, 1H), 3.02-3.09 (m, 1H), 3.21-3.33 (m, 1H), 3.80 (s, 3H), 3.96-4.04(m, 1H), 4.26-4.38 (m, 2H), 6.80-6.95 (m, 6H), 7.16-7.23 (m, 2H).

Example 43-(4-Chlorophenyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15mmol), 3-(4-chloro-phenyl)piperidine (38 mg, 0.165 mmol) andtriethylamine (38 mg, 0.38 mmol) in acetonitrile (2 ml) was heated in amicrowave reactor at 110-150° C. for 290 min. After evaporation todryness, the crude product was purified by flash chromatography using agradient of heptane and EtOAc as eluent to give 36 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.35-1.48 (m, 1H), 1.63-1.83 (m, 2H), 1.86-1.94 (m,1H), 2.06-2.24 (m, 2H), 2.53-2.65 (m, 1H), 2.66-2.75 (m, 1H), 2.77-2.86(m, 1H), 2.90-2.97 (m, 1H), 2.99-3.08 (m, 1H), 3.95-4.03 (m, 1H),4.26-4.37 (m, 2H), 6.78-6.91 (m, 4H), 7.13-7.20 (m, 2H), 7.23-7.30 (m,2H).

Example 51-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-methoxyphenyl)piperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16mmol), 3-(3-methoxyphenyl)piperidine HCl (36 mg, 0.16 mmol) andtriethylamine (40 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in amicrowave reactor at 140-150° C. for 300 min. After evaporation todryness, the crude product was purified by flash chromatography using agradient of heptane and EtOAc as eluent to give 17 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.39-1.51 (m, 1H), 1.67-1.83 (m, 2H), 1.89-1.96 (m,1H), 2.07-2.25 (m, 2H), 2.53-2.64 (m, 1H), 2.68-2.75 (m, 1H), 2.76-2.87(m, 1H), 2.91-3.02 (m, 1H), 3.03-3.09 (m, 1H), 3.80 (s, 3H), 3.95-4.04(m, 1H), 4.28-4.38 (m, 2H), 6.74-6.90 (m, 7H), 7.22 (t, 1H).

Example 6 1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-p-tolylpiperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16mmol), 3-(4-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) andtriethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in amicrowave reactor at 140-150° C. for 9 h. The mixture was absorbed onsilica and purified by flash chromatography using a gradient of heptaneand EtOAc as eluent to give 20 mg of the title compound.

¹H NMR (CDCl₃): δ 1.38-1.50 (m, 1H), 1.65-1.83 (m, 2H), 1.86-1.96 (m,1H), 2.06-2.23, (m, 2H), 2.32 (s, 3H), 2.53-2.63 (m, 1H), 2.67-2.75 (m,1H), 2.75-2.85 (m, 1H), 2.91-3.00 (m, 1H), 3.01-3.09 (m, 1H), 3.95-4.03(m, 1H), 4.27-4.37 (m, 2H), 6.79-6.90 (m, 4H), 7.09-7.15 (m, 4H).

Example 71-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(4-methoxyphenyl)piperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15mmol), 3-(4-methoxyphenyl)piperidine.HCl (38 mg, 0.17 mmol) andtriethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in amicrowave reactor at 160° C. for 3 h. The mixture was absorbed on silicaand purified by flash chromatography using a gradient of heptane andEtOAc as eluent to give 18 mg of the title compound.

¹H NMR (CDCl₃): δ 1.33-1.45 (m, 1H), 1.62-1.82 (m, 2H), 1.83-1.94 (m,1H), 2.05-2.20 (m, 2H), 2.51-2.65 (m, 1H), 2.66-2.82 (m, 2H), 2.90-2.99(m, 1H), 2.99-3.09 (m, 1H), 3.78 (s, 3H), 3.93-4.03 (m, 1H), 4.26-4.38(m, 2H), 6.80-6.93 (m, 6H), 7.10-7.20 (m, 2H).

Example 8 1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-o-tolylpiperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15mmol), 3-(2-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) andtriethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in amicrowave reactor at 140-150° C. for 12.5 h. The mixture was absorbed onsilica and purified by flash chromatography using a gradient of heptaneand EtOAc as eluent to give 29 mg of the title compound.

¹H NMR (CDCl₃): δ 1.40-1.53 (m, 1H), 1.72-1.90 (m, 3H), 2.10-2.27 (m,2H), 2.36 (s, 3H), 2.53-2.65 (m, 1H), 2.69-2.76 (m, 1H), 2.90-3.11 (m,3H), 3.95-4.03 (m, 1H), 4.28-4.37 (m, 2H), 6.80-6.91 (m, 4H), 7.08-7.24(m, 4H).

Example 94-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (47 mg, 0.20mmol), 4-(piperidin-3-yl)phenol.HBr (53 mg, 0.20 mmol) and KHCO₃ (84 mg,0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at160° C. for 6.5 h. The mixture was absorbed on silica and purified byflash chromatography using a gradient of DCM and MeOH as eluent to give6 mg of the title compound.

¹H NMR (CD₃OD): δ 1.38-1.45 (m, 1H), 1.67-1.90 (m, 3H), 2.07-2.21 (m,2H), 2.56-2.79 (m, 3H), 2.93-3.14 (m, 2H), 3.89-3.96 (m, 1H), 4.24-4.29(m, 1H), 4.39-4.39 (m, 1H), 6.68-6.73 (m, 2H), 6.76-6.84 (m, 4H),7.01-7.08 (m, 2H).

Example 101-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-fluorophenyl)piperidine

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (340 mg, 0.48mmol), 3-(3-fluorophenyl)piperidine (323 mg, 2.50 mmol) andtriethylamine (455 mg, 4.50 mmol) in acetonitrile (3 mL) was heated in amicrowave reactor at 140° C. for 60 min. The mixture was absorbed onsilica and purified by flash chromatography using a gradient of heptaneand EtOAc as eluent to give 213 mg of the title compound.

¹H NMR (CDCl₃): δ 1.35-1.50 (m, 1H), 1.64-1.83 (m, 2H), 1.88-1.97 (m,1H), 2.08-2.25 (m, 2H), 2.53-2.65 (m, 1H), 2.67-2.75 (m, 1H), 2.79-2.89(m, 1H), 2.89-2.99 (m, 1H), 2.99-3.09 (m, 1H), 3.95-4.04 (m, 1H),4.28-4.38 (m, 2H), 6.80-6.98 (m, 6H), 6.97-7.01 (m, 7H), 7.21-7.29 (m,1H).

Example 113-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24mmol), 3-(piperidin-3-yl)phenol.HBr (60 mg, 0.23 mmol) and KHCO₃ (84 mg,0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at160° C. for 5.5 h. The mixture was absorbed on silica and purified byflash chromatography using a gradient of DCM and MeOH (1% triethylamine)as eluent to give 74 mg of the title compound.

¹H NMR (CDCl₃): δ 1.38-1.53 (m, 1H), 1.68-1.84 (m, 2H), 1.87-1.97 (m,1H), 2.06-2.24 (m, 2H), 2.53-2.65 (m, 1H), 2.66-2.75 (m, 1H), 2.77-2.86(m, 1H), 2.90-2.97 (m, 1H), 2.99-3.08 (m, 1H), 3.95-4.03 (m, 1H),4.26-4.37 (m, 2H), 6.78-6.91 (m, 4H), 7.13-7.20 (m, 2H), 7.23-7.30 (m,2H).

Example 122-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24mmol), 2-(piperidin-3-yl)phenol —HBr (61 mg, 0.24 mmol) and KHCO₃ (84mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactorat 160° C. for 5.5 h. The mixture was absorbed on silica and purified byflash chromatography using a gradient of DCM and MeOH (1% triethylamine)as eluent to give 11 mg of the title compound.

¹H NMR (CDCl₃): δ 1.51-1.63 (m, 1H), 1.69-1.87 (m, 3H), 2.20-2.41 (m,2H), 2.57-2.75 (m, 2H), 2.86-3.14 (m, 2H), 2.66-2.75 (m, 1H), 3.22-3.31(m, 1H), 3.88-3.95 (m, 1H), 4.24-4.30 (m, 1H), 4.31-4.39 (m, 1H)6.78-6.91 (m, 4H), 7.13-7.20 (m, 2H), 7.23-7.30 (m, 2H).

Example 13(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(2-fluorophenyl)piperidin-1-yl]methanone(10 mg, 0.0035 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 2.7 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.45-1.57 (m, 1H), 1.73-1.81 (m, 2H), 1.87-1.94 (m,1H), 2.18-2.29 (m, 2H), 2.59-2.68 (m, 1H), 2.68-2.75 (m, 1H), 2.76-2.85(m, 1H), 2.91-2.98 (m, 1H), 3.00-3.09 (m, 1H), 3.97-4.06 (m, 1H),4.28-4.37 (m, 2H), 6.79-6.80 (m, 4H), 6.97-7.05 (m, 1H), 7.06-7.12 (m,1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 1H).

Example 14(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(2-fluorophenyl)piperidin-1-yl]methanone(25 mg, 0.073 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 18 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.44-1.57 (m, 1H), 1.61-1.82 (m, 2H), 1.84-1.94 (m,1H), 2.11-2.17 (m, 1H), 2.22-2.32 (m, 1H), 2.55-2.61 (m, 1H), 2.68-2.76(m, 1H), 2.92-2.98 (m, 1H), 3.01-3.08 (m, 1H), 3.14-3.24 (m. 1H),3.96-4.06 (m, 1H), 4.28-4.38 (m, 2H), 6.79-6.92 (m, 4H), 6.98-7.30 (m,4H).

Example 15(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluorophenyl)piperidin-1-yl]methanone(1.21 g, 3.51 mmol) was treated with BH₃ THF according to the abovegeneral procedure. 1.28 g crude product was obtained.

¹H NMR (CDCl₃): δ 1.45-1.57 (m, 1H), 1.73-1.81 (m, 2H), 1.87-1.94 (m,1H), 2.18-2.29 (m, 2H), 2.59-2.68 (m, 1H), 2.68-2.75 (m, 1H), 2.76-2.85(m, 1H), 2.91-2.98 (m, 1H), 3.00-3.09 (m, 1H), 3.97-4.06 (m, 1H),4.28-4.37 (m, 2H), 6.79-6.80 (m, 4H), 6.97-7.05 (m, 1H), 7.06-7.12 (m,1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 1H).

Example 16(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine.HCl

(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine(1.28 g, 3.91 mmol) was treated with large excess of 8% HCl/EtOAC andevaporated to dryness. The crude salt was dissolved in boilingEtOAC/IPA. A precipitate was formed upon cooling. Filtration gave 657 mgof the title compound.

¹H NMR (CDCl₃): δ 1.45-1.57 (m, 1H), 1.73-1.81 (m, 2H), 1.87-1.94 (m,1H), 2.18-2.29 (m, 2H), 2.59-2.68 (m, 1H), 2.68-2.75 (m, 1H), 2.76-2.85(m, 1H), 2.91-2.98 (m, 1H), 3.00-3.09 (m, 1H), 3.97-4.06 (m, 1H),4.28-4.37 (m, 2H), 6.79-6.80 (m, 4H), 6.97-7.05 (m, 1H), 7.06-7.12 (m,1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 1H).

Example 17(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-fluorophenyl)piperidin-1-yl]methanone(19 mg, 0.056 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 11 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.38-1.49 (m, 1H), 1.65-1.82 (m, 2H), 1.88-1.97 (m,1H), 2.07-2.25 (m, 2H), 2.53-2.63 (m, 1H), 2.67-2.76 (m, 1H), 2.80-2.90(m, 1H), 2.92-3.10 (m, 2H), 3.94-4.04 (m, 1H), 4.27-4.40 (m, 2H),6.76-7.04 (m, 7H), 7.20-7.30 (m, 1H).

Example 18(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-fluorophenyl)piperidin-1-yl]methanone(20 mg, 0.058 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 16 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.35-1.48 (m, 1H), 1.64-1.82 (m, 2H), 1.86-1.94 (m,1H), 2.07-2.24 (m, 2H), 2.57-2.65 (m, 1H), 2.66-2.75 (m, 1H), 2.76-2.85(m, 1H), 2.91-2.98 (m, 1H), 3.00-3.09 (m, 1H), 3.95-4.08 (m, 1H),4.28-4.38 (m, 2H), 6.80-6.89 (m, 4H), 6.94-7.03 (m, 2H), 7.16-7.23 (m,2H).

Example 19(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-fluorophenyl)piperidin-1-yl]methanone(20 mg, 0.058 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave the title compound.

¹H NMR (CDCl₃): δ 1.35-1.43 (m, 1H), 1.65-2.23 (m, 3H), 2.05-2.22 (m,2H), 2.53-2.62 (m, 1H), 2.67-2.75 (m, 1H), 2.77-2.88 (m, 1H), 2.92-3.00(m, 1H), 3.00-3.10 (m, 1H), 3.93-4.03 (m, 1H), 4.28-4.40 (m, 2H),6.81-6.92 (m, 4H), 6.95-7.03 (m, 2H), 7.15-7.24 (m, 2H).

Example 20(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]methanone(30 mg, 0.077 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 16 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.40-1.55 (m, 1H), 1.65-1.85 (m, 2H), 1.89-1.99 (m,1H), 2.15-2.28 (m, 2H), 2.59-2.64 (m, 1H), 2.70-2.77 (m, 1H), 2.84-2.99(m, 2H), 3.03-3.12 (m, 1H), 3.98-4.04 (m, 1H), 4.29-4.38 (m, 2H),6.78-6.90 (m, 4H), 7.38-7.54 (m, 4H).

Example 21(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]methanone(29 mg, 0.074 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 15 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.40-1.55 (m, 1H), 1.61-1.87 (m, 2H), 1.87-1.99 (m,1H), 2.09-2.30 (m, 2H), 2.52-2.64 (m, 1H), 2.66-2.77 (m, 1H), 2.84-3.12(m, 3H), 3.94-4.07 (m, 1H), 4.24-4.41 (m, 2H), 6.78-6.96 (m, 4H),7.36-7.53 (m, 4H).

Example 22(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (18 mg, 0.046 mmol) wastreated with BH₃ THF according to the above general procedure. Flashchromatography gave 7.6 mg of the title compound.

¹H NMR (CDCl₃): δ 1.40-1.52 (m, 1H), 1.68-1.84 (m, 2H), 1.80-1.98 (m,1H), 2.15-2.27 (m, 2H), 2.59-2.65 (m, 1H), 2.67-2.76 (m, 1H), 2.86-3.00(m, 2H), 3.01-2.15 (m, 1H), 3.95-4.01 (m, 1H), 4.29-4.37 (m, 2H),6.78-6.93 (m, 4H), 7.31-7.39 (m, 2H), 7.51-7.59 (m, 2H).

Example 23(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone(13 mg, 0.033 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 6 mg of the title compound.

¹H NMR (CDCl₃): δ 1.39-1.53 (m, 1H), 1.65-1.86 (m, 2H), 1.88-1.97 (m,1H), 2.09-2.29 (m, 2H), 2.55-2.64 (m, 1H), 2.68-2.77 (m, 1H), 2.84-3.11(m, 3H), 195-4.05 (m, 1H), 4.27-4.38 (m, 2H), 6.78-6.95 (m, 4H),7.31-7.38 (m, 2H), 7.51-7.61 (m, 2H).

Example 24(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone(21 mg, 0.059 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 7.0 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.40-1.51 (m, 1H), 1.69-1.82 (m, 2H), 1.89-1.96 (m,1H), 2.15-2.23 (m, 2H), 2.56-2.64 (m, 1H), 2.67-2.75 (m, 1H), 2.75-2.85(m, 1H), 2.91-2.84 (m, 1H), 3.02-3.10 (m, 1H), 3.80 (s, 3H), 3.95-4.01(m, 1H), 4.28-4.35 (m, 2H), 6.73-6.92 (m, 7H), 7.19-7.25 (m, 1H).

Example 25(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine.HCl

Crude(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine(2.5 g) was treated three times with 8% HCl/EtOAc and evaporated todryness. After crystallisation from hot EtOAc/IPA (10 ml/2.5 ml), 1.24 gof the title compound was obtained as almost white crystals.

¹H NMR (CD₃OD): δ 1.72-1.88 (m, 1H), 1.93-2.22 (m, 3H), 3.04-3.27 (m,4H), 3.39-3.56 (m, 2H), 3.64-3.79 (m, 2H), 3.99-4.08 (m, 1H), 4.29-4.35(m, 1H), 4.29-4.40 (m, 1H), 4.75-4.90 (m, 1H), 6.84-6.94 (m, 4H),7.00-7.17 (m, 3H), 7.34-7.43 (m, 1H).

Example 26(S*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone(21 mg, 0.059 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave 7.0 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.38-1.52 (m, 1H), 1.67-1.83 (m, 2H), 1.88-1.97 (m,1H), 2.06-2.16, (m, 1H), 2.16-2.25 (m, 1H), 2.53-2.61 (m, 1H), 2.69-2.75(m, 1H), 2.76-2.87 (m, 1H), 2.94-3.01 (m, 2H), 3.80 (s, 3H), 3.93-4.02(m, 1H), 4.27-4.37 (m, 2H), 6.71-6.90 (m, 7H), 7.18-7.27 (m, 1H).

Example 27(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxyphenyl)piperidin-1-yl]-methanone(17.8 g, 54.7 mmol) was treated with BH₃ THF according to the abovegeneral procedure. Crystallisation from hot EtOH gave 8.5 g of the titlecompound as almost white crystals.

¹H NMR (CD₃OD): δ 1.40-1.54 (m, 1H), 1.71-1.82 (m, 2H), 1.84-1.93 (m,1H), 2.12-2.23 (m, 2H), 2.59-2.74 (m, 2H), 2.74-2.83 (m, 1H), 2.99-3.14(m, 1H), 3.92-3.98 (m, 1H), 4.24-4.31 (m, 1H), 4.33-4.39 (m, 1H),6.59-6.63 (m, 1H), 6.66-6.68 (m, 1H), 6.69-6.74 (m, 1H), 6.76-6.83 (m,4H), 7.06-7.12 (m, 1H).

Example 28(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol.HCl

(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxyphenyl)piperidin-1-yl]-methanone(200 mg, 0.615 mmol) was dissolved in EtOAc (4 ml). 1 M HCl/diethylether was added in excess. The precipitate was filtered to give 172 mgof the desired salt.

¹H NMR (CDCl₃): δ 1.52-1.62 (m, 1H), 1.89-2.11 (m, 2H), 2.35-2.53 (m,1H), 2.69-2.96, (m, 2H), 3.10-3.21 (m, 1H), 3.35-3.62 (m, 3H), 3.89-4.00(m, 1H), 4.07-4.15 (m, 1H), 4.20-4.32 (m, 1H), 6.64-6.72 (m, 1H),6.80-7.01 (m, 7H), 7.12-7.19 (m, 1H), 12.45 (br, 1H).

Example 29(3-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol(R*)-3-[1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)piperidin-3-yl]benzoicacid methyl ester

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (240 mg, 1.21 mmol)in DCM (5 ml) was added to an ice-cold mixture of3-(piperidin-3-yl)benzoic acid methyl ester (267 mg, 1.21 mmol),triethylamine (59 mg, 0.58 mmol) and DCM (10 ml). After stirring for 2 hat RT, the mixture was washed with 1 M HCl (10 ml) and 1 M Na₂CO₃. Theorganic phase was dried over Na₂SO₄ and evaporated to dryness and theresidue was purified by flash chromatography using heptane/EtOAc aseluent. The first eluting diastereomer was collected to afford 98 mg ofthe title compound.

¹H NMR (CDCl₃): δ 1.72-2.02 (m, 3H), 2.09-2.19 (m, 1H), 2.65-2.89 (m,2H), 3.07-3.19 (m, 0.6H), 3.24-3.33 (m, 0.4H), 3.92 (s, 3H), 4.16-4.27(m, 1H), 4.30-4.39 (m, 1H), 4.48-4.54 (m, 1H), 4.68-4.76 (m, 1H),4.76-4.89 (m, 1H) 6.79-6.99 (m, 4H), 7.38-7.46 (m, 2H), 7.90-7.73 (m,2H).

(3-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol

((R*)-3-[1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)piperidin-3-yl]benzoicacid methyl ester (54 mg, 0.147 mmol) was dissolved in dry THF (4 ml)and cooled to 0° C. LiAlH₄ (26 mg, 0.680 mmol) was added and the mixturewas stirred at RT for 2 h. Water (1 ml), 1 M NaOH (1 ml) and again water(1 ml) were added slowly. The mixture was filtered through Celite andevaporated. Flash chromatography, using a gradient of heptane/EtOAc,gave 3.5 mg of the title compound.

¹H NMR (CDCl₃): δ 1.47-1.60 (m, 1H), 1.72-1.85 (m, 2H), 1.89-1.96 (m,1H), 2.17-2.26 (m, 2H), 2.60-2.74 (m, 2H), 2.59-2.75 (m, 2H), 2.82-2.91(m, 1H), 4.06-4.14 (m, 1H), 4.25-4.31 (m, 1H), 4.32-4.30 (m, 1H), 4.58(s, 2H), 6.75-6.85 (m, 4H), 7.13-7.22 (m, 2H), 7.23-7.35 (m, 2H).

Example 30 Acetic acid3-{(S)-1-[(R*)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenylester.HCl

Acetyl chloride (58 mg, 0.74 mmol) was added to a solution of(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo-[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(198 mg, 0.608 mmol) and triethylamine (75 mg, 0.74 mmol) in DCM (5 ml).The mixture was stirred for 40 min, washed with water, dried over Na₂SO₄and evaporated to dryness. The crude product was treated with excessEtOAc/HCl and evaporated to dryness. Recrystallisation from hotEtOAc/IPA gave 60 mg of the title compound.

¹H NMR (CD₃OD): δ 1.69-1.85 (m, 1H), 1.91-2.18 (m, 3H), 2.28 (s, 3H),3.05-3.36 (m, 4H), 3.45-3.60 (m, 1H), 3.64-3.86 (m, 1H), 4.00-4.08 (m,1H), 4.25-4.42 (m, 1H), 4.71-4.80 (m, 2H), 6.84-6.94 (m, 4H), 7.01-7.10(m, 2H), 7.18-7.23 (m, 1H), 7.37-7.43 (m, 1H).

Example 312-(3-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanol

(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(51 mg), K₂CO₃ (28 mg, 0.20 mmol), 2-chloroethanol and MeCN (2 ml) wereheated under microwaves at 80-105° C. for 6 h. The solvent was removedand the residue was taken up in DCM. This solution was washed with waterand 1 M NaOH and evaporated to dryness. Flash chromatography(heptane/EtOAc) gave 3 mg of the title compound.

¹H NMR (CD₃OD): δ 1.44-1.56 (m, 1H), 1.69-1.84 (m, 2H), 1.85-1.94 (m,1H), 2.14-2.26 (m, 2H), 2.58-2.74 (m, 2H), 2.76-2.87 (m, 1H), 2.98-3.16(m, 2H), 3.83-3.89 (m, 2H), 3.89-3.97 (m, 2H), 3.99-4.06 (m, 2H),4.24-4.31 (m, 1H), 4.33-4.39 (m, 1H), 6.76-6.88 (m, 7H), 7.16-7.23 (m,1H).

Example 323-(3-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-ol

(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(208 mg, 0.64 mmol), K₂CO₃ (103 mg, 0.74 mmol), 3-bromo-1-propanol (86mg, 0.62 mmol) and MeCN (5 ml) were heated under microwaves at 105° C.for 6 h. More K₂CO₃ (103 mg) and 3-bromo-1-propanol (86 mg) were addedand the heating was continued for 2 h. The solvent was removed and theresidue was taken up in DCM. This solution was washed with water and 1 MNaOH and evaporated to dryness. Flash chromatography (heptane/EtOAc)gave 76 mg of the title compound.

¹H NMR (CD₃OD): δ 1.44-1.56 (m, 1H), 1.64-1.84 (m, 2H), 1.84-1.93 (m,1H), 1.93-2.00 (m, 2H), 2.15-2.26 (m, 2H), 2.59-2.74 (m, 2H), 2.76-2.86(m, 1H), 2.98-3.16 (m, 2H), 3.70-3.76 (m, 2H), 3.90-3.97 (m, 1H),4.02-4.09 (m, 2H), 4.25-4.30 (m, 1H), 4.32-4.38 (m, 1H), 6.72-6.84 (m,7H), 7.14-7.22 (m, 1H).

Example 33 Trifluoromethanesulfonic acid3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenylester

(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(1.77 g, 5.44 mmol) was dissolved in DCM (10 ml) under an inertatmosphere. Triethylamine (0.58 g, 5.71 mmol) was added and the mixturewas cooled to −30° C. Trifluoromethanesulfonic acid anhydride (1.61 g,5.71 mmol) was added dropwise. The cooling bath was removed and themixture stirred for 1 h. The mixture was washed with water (2×10 ml) andevaporated to dryness. Column chromatography, using a gradient ofDCM:MeOH as eluent, gave 1.1 g of the title compound.

¹H NMR (CDCl₃): δ 1.38-1.51 (m, 1H), 1.65-1.84 (m, 2H), 1.89-1.99 (m,1H), 2.11-2.28 (m, 2H), 2.57-2.64 (m, 1H), 2.68-2.75 (m, 1H), 2.83-3.09(m, 3H), 3.96-4.03 (m, 1H), 4.26-4.38 (m, 2H), 6.80-6.92 (m, 4H),7.08-7.18 (m, 2H), 7.25-7.34 (m, 1H), 7.36-7.41 (m, 1H).

Example 34(3-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)aceticacid

To a solution of(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(201 mg, 0.62 mmol) in dry DMF (2 ml) was added NaH (60% in oil, 30 mg,0.75 mmol) under nitrogen atmosphere and the mixture was stirred at 0°C. for 5 min, then allowed to warm to RT and stirred for further 2.5 h.The reaction mixture was cooled to 0° C., ethyl bromoacetate (106 mg,0.62 mmol) was added and the mixture was stirred at RT overnight.Potassium tert-butoxide (69 mg, 0.61 mmol) was added and the mixture wasstirred for 3 h at RT and filtered. The precipitate was dissolved in dryMeOH, the solution filtered and evaporated to dryness to give 170 mg ofthe title compound.

¹H NMR (DMSO-d₆): δ 1.33-1.46 (m, 1H), 1.52-1.73 (m, 2H), 1.74-1.83 (m,1H), 2.04-2.17 (m, 2H), 2.56-2.73 (m, 3H), 2.88-2.98 (m, 2H), 3.93-3.99(m, 1H), 4.06 (s, 2H), 4.27-4.39 (m, 2H), 6.59-6.64 (m, 1H), 6.69-6.88(m, 6H), 7.11 (t, 1H, J=6.8 Hz).

Example 353-{(R*)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-benzonitrile

A mixture of trifluoromethanesulfonic acid3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenylester (51 mg, 0.11 mmol), tributyltin cyanide (142 mg, 0.45 mmol) andtetrakis(triphenylphosphine)palladium (189 mg, 0.164 mmol) in1,2-dichloroethane (15 ml) was heated in a microwave reactor at 80° C.for 80 h. The solid precipitate was filtered off and the mixture wasevaporated to dryness. The residue was redissolved in DCM, filtered andwashed two times with 1 M HCl. The combined organic phases were washedwith brine, dried (Na₂SO₄) and evaporated to dryness. The crude productwas purified by flash chromatography first using gradient of DCM andMeOH and then using gradient of heptane and EtOAc as eluent to give 2.8mg of the title compound.

¹H NMR (CDCl₃): δ 1.48-1.59 (m, 1H), 1.70-1.84 (m, 2H), 1.89-1.94 (m,1H), 2.19-2.32 (m, 2H), 2.61-2.75 (m, 2H), 2.89-3.10 (m, 3H), 3.93-3.98(m, 1H), 4.26-4.35 (m, 1H), 4.35-4.40 (m, 1H), 6.76-6.84 (m, 3H),7.43-7.60 (m, 5H).

Example 363-Benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine3-Benzo[1,3]dioxol-5-ylpyridine

A mixture of 3,4-(methylenedioxy)phenylboronic acid (500 mg, 3.0 mmol),3-bromopyridine (290 μl, 476 mg, 3.0 mmol), 2 M Na₂CO₃ (3.05 ml, 6.0mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), EtOH(0.75 ml) and toluene (3 ml) was heated in a microwave reactor at 120°C. for 40 min. Another crop of 3,4-(methylenedioxy)phenylboronic acid(250 mg, 1.5 mmol) was added and the mixture heated under microwaves at120° C. for 10 min. The reaction mixture was filtered and the layerswere separated. The organic phase was extracted twice with 1 M HCl. Allthe aqueous phases were combined, basified with 5 M NaOH and extractedtwice with EtOAc. The combined organic phases were dried (Na₂SO₄),filtered and evaporated to give 585 mg of the title compound.

¹H NMR (DMSO-d₆): δ 6.08 (s, 2H), 7.03-7.06 (m, 1H), 7.19-7.24 (m, 1H),7.33-7.35 (m, 1H), 7.42-7.46 (m, 1H), 7.99-8.03 (m, 1H), 8.52 (dd, 1H,J=1.77, 4.80 Hz), 8.84 (dd, 1H, J=2.65, 0.88 Hz).

3-Benzo[1,3]dioxol-5-ylpiperidine.HCl

3-Benzo[1,3]dioxol-5-ylpyridine (578 mg, 2.9 mmol), PtO₂ hydrate (58mg), methanol (20 ml) and conc. HCl (2 ml) were charged into the Parrreaction flask and hydrogenated (55 psi) for 4 h. The reaction mixturewas filtered and evaporated to dryness. The crude product wascrystallized from EtOAc/IPA to give 226 mg of the title compound.

¹H NMR (CD₃OD): δ 1.71-1.91 (m, 2H), 1.96-2.08 (m, 2H), 2.85-2.95 (m,1H), 2.96-3.06 (m, 2H), 3.32-3.46 (m, 2H), 5.92 (s, 2H), 6.73-6.83 (m,3H).

(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone

A mixture of (R)-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (167 mg,0.93 mmol), thionyl chloride (338 μl, 551 mg, 4.63 mmol) and dry toluenewas heated at 95° C. for 1.5 h and then evaporated to dryness. Toluenewas added and the evaporation was repeated. The evaporation residue wasdissolved in DCM (2 ml) and added slowly to a cold solution (0° C.) of3-benzo[1,3]dioxol-5-yl-piperidine HCl (224 mg, 0.93 mmol) and DIPEA(0.324 ml, 240 mg, 1.85 mmol) in DCM (5 ml). The reaction mixture wasstirred for 1 h 45 min at RT. Water was added, layers were separated andthe organic phase was washed twice with 1 M HCl and sat. NaHCO₃. Theorganic phase was dried (Na₂SO₄), filtered and evaporated to give 290 mgof the title compound.

¹H NMR (CDCl₃): δ 1.56-1.77 (m, 2H), 1.82-1.97 (m, 1H), 2.03-2.14 (m,1H), 2.52-2.73 (m, 2H), 2.85-3.25 (m, 1H), 4.10-4.22 (m, 1H), 4.29-4.38(m, 1H), 4.45-4.55 (m, 1H), 4.63-4.73 (m, 1H), 4.78-4.91 (m, 1H), 5.94(s, 2H), 6.64-6.97 (m, 7H).

3-Benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine

(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone(285 mg, 0.77 mmol) was dissolved in dry DMF (2.5 ml) and 1 M BH₃ THF(3.10 ml, 3.10 mmol) was slowly added under a nitrogen atmosphere. Thereaction mixture was stirred for 4.5 h at RT and then cooled to 0° C.Water was slowly added and the mixture basified with 2.5 M NaOH andextracted three times with EtOAc. The combined organic phases were dried(Na₂SO₄), filtered and evaporated to dryness. The crude product wasdissolved in methanol (25 ml) and 5 M HCl (1.5 ml) was slowly added. Themixture was stirred for 1 h at RT and then at 60° C. for 2 h. Thereaction mixture was evaporated to dryness, redissolved in EtOAc andwashed twice with 1 M Na₂CO₃ and water. The combined organic phases weredried (Na₂SO₄), filtered and evaporated to dryness to give 228 mg of thetitle compound.

¹H NMR (CDCl₃): δ 1.33-1.46 (m, 1H), 1.63-1.82 (m, 2H), 1.85-1.94 (m,1H), 2.05-2.21. (m, 2H), 2.53-2.63 (m, 1H), 2.66-2.81 (m, 2H), 2.90-2.98(m, 1H), 2.98-3.07 (m, 1H), 3.94-4.03 (m, 1H), 4.27-4.36 (m, 2H), 5.92(s, 2H), 6.66-6.71 (m, 1H), 6.72-6.76 (m, 2H), 6.79-6.90 (m, 4H).

Example 373-[(R*)-1-((S)-6-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol1-[4-Benzyloxy-24(R)-1-oxiranylmethoxy)phenyl]ethanone

To a stirred solution of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethanone (3.36g, 13.9 mmol) in anhydrous DMF (15 ml) was added NaH (0.62 g, 15.5mmol). The mixture was allowed to stir at RT for 30 min, and a solutionof (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (3.17 g, 13.9 mmol) inDMF was added dropwise at RT. The mixture was slowly heated to 60° C.and stirred for 3 h. The reaction was quenched by addition of water (80ml) and extracted three times with EtOAc. The combined organic layerswere extracted twice with aq 1 M NaOH and washed with water and brine.The organic layer was dried with Na₂SO₄ and concentrated. The crudeproduct obtained was purified by column chromatography withEtOAc/heptane (1:1) as eluent to afford the title compound (2.64 g) as awhite solid.

¹H NMR (CDCl₃): δ 2.63 (s, 3H), 2.76 (m, 1H), 2.94 (t, 1H), 3.39 (m,1H), 3.96 (dd, 1H), 4.32 (dd, 1H), 5.10 (s, 2H), 6.52 (d, 1H), 6.62 (dd,1H), 7.34-7.44 (m, 5H), 7.84 (d, 1H).

Acetic acid 4-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester

To a stirred solution of1-[4-benzyloxy-2((R)-1-oxiranylmethoxy)phenyl]ethanone (1.62 g, 5.43mmol) in DCM (60 ml) was added m-chloroperbenzoic acid (2.15 g) andsolid NaHCO₃ (3.24 g). Stirring was continued at 40° C. for 1 h. Themixture was filtered and the filtrate was washed once with 10% NaHSO₄solution and then twice with NaHCO₃ solution. The organic layer waswashed with water and brine, dried with Na₂SO₄. The solvent was removedunder reduced pressure. The crude product obtained (1.34 g) wassufficiently pure for the next step.

¹H NMR (CDCl₃): δ 2.30 (s, 3H), 2.71 (m, 1H), 2.87 (t, 1H), 3.30 (m,1H), 3.94 (dd, 1H), 4.21 (dd, 1H), 5.02 (s, 2H), 6.54 (dd, 1H), 6.64 (d,1H), 6.94 (d, 1H), 7.33-7.42 (m, 5H).

((S)-6-Benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol

To a stirred solution of acetic acid4-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester (1.34 g, 4.26 mmol) inTHF (30 ml), was added aq 2 M NaOH (2.45 ml). The mixture was stirredovernight at RT, THF was removed under reduced pressure and water (50ml) was added. The water solution was then extracted three times withEtOAc and the combined extracts washed with water and brine. The organiclayer was dried (Na₂SO₄), and evaporated in vacuo. The crude product(1.07 g) was used without purification.

¹H NMR (CDCl₃): δ 1.96 (br s, 1H), 3.80-3.91 (m, 2H), 4.08 (m, 1H), 4.11(m, 1H), 4.27 (dd, 1H), 4.99 (s, 2H), 6.50-6.54 (m, 2H), 6.80 (d, 1H),7.30-7.42 (m, 5H).

Methanesulfonic acid(R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester

To a stirred solution of crude((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (1.65 g, 6.06mmol) in dry DCM (10 ml), was added triethylamine (0.88 ml). The mixturewas cooled to 0° C. and methanesulfonyl chloride (0.49 ml) was addedslowly dropwise to reaction mixture. The mixture was stirred at RT for 1h and then 10 ml of aq 1 M HCl was added. The mixture was extractedtwice with DCM. The combined organic layers were washed with water andbrine, dried with Na₂SO₄. The solvents were removed under reducedpressure and the crude product (2.22 g) was crystallized from IPA (15ml), which gave a white solid (1.50 g).

¹H NMR (CDCl₃): δ 3.08 (s, 3H), 4.11 (m, 1H), 4.28 (d, 1H), 4.42 (s,3H), 4.98 (s, 2H), 6.51-6.55 (m, 2H), 6.79 (d, 1H), 7.31-7.42 (m, 5H).

3-[(R*)-1-((S)-6-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol

To a solution of methanesulfonic acid(R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester (129 mg,0.368 mmol) and (R*)-3-(piperidin-3-yl)phenol.HBr (100 mg, 0.387 mmol)in acetonitrile was added solid KI (40 mg) and NaHCO₃(98 mg 1.162 mmol).The mixture was heated under microwave irradiation at 150° C. for 1 h.Solid material was filtered and the solvent was evaporated under reducedpressure. The residue was dissolved to DCM and washed twice with waterand brine. The organic phase was dried (Na₂SO₄), and evaporated invacuo. The residue was purified by flash column chromatography(EtOAc/heptane) to give the desired product (66.2 mg).

¹H NMR (CDCl₃): δ 1.42-1.49 (m, 1H), 1.74-1.77 (m, 2H), 1.91 (d, 1H),2.14-2.20 (m, 2H), 2.59 (dd, 1H), 2.68-2.73 (dd, 1H), 2.79-2.85 (m, 1H),2.97 (d, 1H), 3.13 (d, 1H), 3.96 (dd, 1H), 4.24-4.29 (m, 2H), 4.96 (s,2H), 6.46 (dd, 1H), 6.53 (d, 1H), 6.66-6.80 (m, 4H), 6.75 (1H, m), 7.17(t, 1H), 7.30-7.42 (m, 5H).

Example 38(5)-2-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol

To a solution of 10% Pd/C (33 mg) in EtOAc (10 ml) was added3-[(R*)-1-4S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol(66 mg, 0.125 mmol). The mixture was stirred under hydrogen for 3 h atnormal pressure. The mixture was then filtered and evaporated to give anoil. After trituration with diethyl ether the title compound wasobtained as a white solid (40 mg).

¹H NMR (DMSO-d₆): δ 1.30-1.40 (m, 1H), 1.53-1.69 (m, 2H), 1.78 (d, 1H),2.04-2.11 (m, 2H), 2.56 (m, 2H), 2.61-2.67 (m, 1H), 2.90 (dd, 2H), 3.89(dd, 1H), 4.21-4.26 (m, 2H), 6.20-6.25 (m, 2H), 6.57-6.68 (m, 4H), 7.06(t, 1H), 8.90 (s, 1H), 9.21 (s, 1H).

Example 393-[(R*)-1-((S)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol1-[5-Benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone

To a stirred solution of 1-(5-benzyloxy-2-hydroxyphenyl)ethanone (3.0 g,12.4 mmol) in anhydrous DMF (15 ml) was added NaH (0.55 g, 13.6 mmol).The mixture was allowed to stir at RT for 30 min and then heated to 60°C. A solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (2.83 g,12.4 mmol) in DMF was added dropwise at 60° C. during 1 h. Stirring wasthen continued at 60° C. for 3 h. The cooled reaction was quenched byaddition of water (80 ml) and extracted three times with EtOAc. Thecombined organic layers were extracted twice with aq 1 M NaOH and washedwith water and brine. The organic layer was dried with Na₂SO₄ andconcentrated. The crude product obtained was purified by columnchromatography with EtOAc/toluene as eluent to afford the title compound(2.35 g) as a white solid.

¹H NMR (CDCl₃): δ 2.67 (s, 3H), 2.75 (m, 1H), 2.93 (t, 1H), 3.37-3.40(m, 1H), 3.96 (dd, 1H), 4.32 (dd, 1H), 5.04 (s, 2H), 6.89 (d, 1H), 7.08(dd, 1H), 7.32-7.43 (m, 6H).

Acetic acid 5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester

To a stirred solution of1-[5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone (1.0 g, 3.36mmol) in DCM (20 ml) was added m-chloroperbenzoic acid (1.24 g) andsolid NaHCO₃ (3.24 g). The mixture was stirred at RT for 3 d. Themixture was filtered and the filtrate washed once with 10% NaHSO₄solution and then twice with NaHCO₃ solution. The organic layer waswashed with water and brine and dried with Na₂SO₄. The solvent wasremoved under reduced pressure. The residue was triturated with ether togive the title compound (0.55 g) as a white solid, which was usedwithout purification.

¹H NMR (CDCl₃): δ 2.32 (s, 3H), 2.70 (m, 1H), 2.86 (dd, 1H), 3.29-3.30(m, 1H), 3.92 (dd, 1H), 4.19 (dd, 1H), 5.00 (s, 2H), 6.73 (d, 1H), 6.79(dd, 1H), 6.94 (d, 1H), 7.33-7.42 (5H, m).

((S)-7-Benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol

To a stirred solution of acetic acid5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester (0.5 g, 1.59 mmol) inTHF (10 ml) was added aq 2 M NaOH (1.04 ml). After stirring overnight atRT, THF was removed under reduced pressure and water (20 ml) was added.The water solution was then extracted two times with EtOAc. The combinedorganic layers washed with water and brine, dried (Na₂SO₄), andevaporated in vacuo. The crude product (0.45 g) was used withoutpurification.

¹H NMR (CDCl₃): δ 1.89 (t, 1H), 3.83-3.91 (m, 2H), 4.06 (dd, 1H),4.23-4.28 (m, 2H), 4.99 (s, 2H), 6.50 (dd, 1H), 6.56 (d, 1H), 6.79 (d,1H), 7.26-7.41 (m, 5H).

Methanesulfonic acid(R)-7-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester

Prepared according to the procedure described above for methanesulfonicacid (R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester.

¹H NMR (CDCl₃): δ 3.07 (s, 3H), 4.07 (dd, 1H), 4.27 (d, 1H), 4.44-4.49(m, 3H), 4.99 (s, 2H), 6.51-6.54 (m, 2H), 6.81 (d, 1H), 7.32-7.37 (m,5H).

3-[(R*)-1-((S)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol

Prepared according to the procedure described above for3-[(R*)-1-(S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol.

¹H NMR (CDCl₃): δ 1.38-1.48 (m, 1H), 1.75 (m 2H), 1.89 (d, 1H),2.10-2.16 (m, 2H), 2.55 (dd, 1H), 2.70 (dd, 1H), 2.83 (t, 1H), 3.01 (d,1H), 3.11 (d, 1H), 3.90 (dd, 1H), 4.18 (dd, 1H), 4.33-4.38 (m, 1H), 4.99(s, 2H), 6.43-6.78 (m, 6H), 7.14 (t, 1H), 7.28-7.41 (m, 5H).

Example 40(S)-3-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol

Prepared according to the procedure described above for(S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol.

¹H NMR (DMSO-d₆): δ 1.33-1.37 (m, 2H), 1.57-1.79 (m, 2H), 2.02-2.12 (m,1H), 2.55-2.67 (m, 2H), 2.91 (dd, 2H), 3.86 (dd, 1H), 4.19 (dd, 1H),4.29 (m, 1H), 6.20-6.22 (m, 2H), 6.57-6.68 (m, 4H), 7.06 (t, 1H), 8.90(s, 1H), 9.21 (s, 1H).

Example 413-[(R*)-1-((S)-8-Benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenolMethanesulfonic acid(R)-8-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester

Prepared according to the procedure described above for methanesulfonicacid (R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester.

¹H NMR (CDCl₃): δ2.96 (s, 3H), 4.08 (dd, 1H), 4.29 (d, 1H), 4.41-4.54(m, 3H), 5.06 (s, 2H), 6.58 (dd, 2H), 6.79 (t, 1H), 7.32-7.41 (m, 5H).

3-[(R*)-1-((S)-8-Benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol

Prepared according to the procedure described above for3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol.

¹H NMR (CDCl₃): δ 1.35-1.45 (m, 1H), 1.71-1.75 (m, 2H), 1.87 (d, 1H),2.20-2.28 (m, 2H), 2.65 (dd, 1H), 2.75-2.80 (m, 2H), 2.94 (d, 1H), 3.10(d 1H), 3.99 (dd, 1H), 4.27 (dd, 1H), 4.37-4.40 (m, 1H), 5.08 (s, 2H),6.49-6.59 (m, 2H), 6.63-6.78 (m, 4H), 7.11 (t, 111), 7.25-7.47 (m, 5H).

Example 42(S)-3-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-5-ol

Prepared according to the procedure described above for(S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol.

¹H NMR (CDCl₃): δ 1.52-1.56 (m, 1H), 1.70-2.17 (m, 4H), 2.14 (t, 1H),2.41 (dd, 1H), 2.93 (dd, 1H), 3.06 (t, 1 h), 3.32-3.35 (m, 2H), 3.89(dd, 1H), 4.25 (dd, 1H), 4.48 (t, 1H), 6.42 (dd, 1H), 6.54 (dd, 1H),6.69-6.77 (m, 2H), 6.85-6.87 (m, 2H), 7.23 (t, 1H), 8.2-8-9 (br, s, 2H).

Example 43(R*)-3-[1-((S)-7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol

A mixture of methanesulfonic acid(R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (51 mg, 0.19mmol), (R*)-3-(piperidin-3-yl)phenol HBr (50 mg, 0.19 mmol) and NaHCO₃(33 mg, 0.39 mmol) in DMF (3.5 ml) was heated at 120° C. for 1.5 h.Water (10 ml) was added to the cooled mixture, which was then extractedwith EtOAc (3×10 ml). The combined organic layers were washed severaltimes with water and finally twice with brine. Drying (Na₂SO₄),filtering and evaporation of the solvent gave the crude product, whichwas recrystallised from EtOH to afford 24 mg of the title compound as awhite solid.

¹H NMR (CDCl₃): δ 1.35-1.82 (m, 4H), 1.92 (br d, 1H), 2.10-2.22 (m, 2H),2.58 (dd, J=13.2 and 6 Hz, 1H), 2.69 (dd, J=13.2 and 6 Hz, 1H),2.75-2.85 (m, 1H), 2.95 (br d, 1H), 3.06 (br d, 1H), 3.92-3.99 (m, 1H),4.25-4.37 (m, 2H), 6.50-6.82 (m, 6H), 7.17 (dd, J=7.5 Hz, 1H).

Example 441-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-methyl-1,2,3,6-tetrahydropyridine

2-Bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol) and3-picoline (203 mg, 2.18 mmol) were refluxed in xylene (2 ml) for 4 h.After cooling, the solvent was decanted to give the crude oilypicolinium salt, which was dissolved in MeOH (5 ml). NaBH₄ (330 mg, 4eq) was added in small portions to the ice cooled mixture. Afterstirring for 2 h at RT, MeOH was evaporated, water was added and themixture extracted with EtOAc. Drying (Na₂SO₄), filtering and evaporationgave the crude product, which was purified by flash chromatography(heptane/EtOAc).

¹H NMR (CDCl₃): δ 1.65 (s, 3H), 2.10-2.18 (m, 2H), 2.50-2.80 (m, 4H),2.86-3.04 (m, 2H), 3.95-4.05 (m, 1H), 4.28-4.40 (m, 2H), 5.45 (m, 1H),6.77-6.90 (m, 4H).

Example 451-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,5-dimethyl-1,2,3,6-tetrahydropyridine

Following the above procedure,2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (856 mg, 3.73 mmol) and3,5-lutidine (400 mg, 3.73 mmol) were refluxed in xylene (2 ml) for 4.5h. Reduction of the crude lutidinium salt with NaBH₄ in MeOH gave thecrude title product, which was purified by flash chromatography(heptane/EtOAc).

¹H NMR (CDCl₃): δ 0.95 (d, J=7 Hz, 3H), 1.64 (s, 3H), 2.08 (m, 1H), 2.35(m, 1H), 2.60-3.08 (m, 5H), 3.95-4.03 (m, 1H), 4.28-4.37 (m, 2H), 5.31(s, 1H), 6.78-6.90 (m, 4H).

Example 46[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,5,6-tetrahydropyridin-3-yl]methanol

As above, 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol)and pyridin-3-ylmethanol (238 mg, 2.18 mmol) were refluxed in xylene (2ml) for 4 h. Reduction of the crude pyridinium salt with NaBH₄ in MeOHgave the crude title product, which was purified by flash chromatography(heptane/EtOAc).

¹H NMR (CDCl₃): δ 2.15-2.25 (m, 2H), 2.55-2.82 (m, 4H), 3.03-3.18 (m,2H), 3.95-4.05 (m, 1H), 4.03 (s, 2H), 4.27-4.40 (m, 2H), 5.75 (m, 1H),6.77-6.90 (m, 4H).

Example 472-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

As above, 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol)and 5,6,7,8-tetra-hydroisoquinoline (290 mg, 2.18 mmol) were refluxed inxylene (2 ml) for 4 h. Reduction of the crude tetrahydroisoquinoliniumsalt with NaBH₄ in MeOH gave the crude title product, which was purifiedby flash chromatography (heptane/EtOAc).

¹H NMR (CDCl₃): δ 1.50-1.65 (m, 4H), 1.77-1.92 (m, 4H), 2.03 (m, 2H),2.55-2.78 (m, 4H), 2.80-2.98 (m, 2H), 3.95-4.02 (m, 1H), 4.30-4.38 (m,2H), 6.78-6.90 (m, 4H).

Example 482-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)decahydroisoquinoline

The above described2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4,5,6,7,8-octahydroiso-quinoline(195 mg, 0.68 mmol) was hydrogenated in MeOH (20 ml) under normalpressure (12 h, 50° C.) to give the crude title compound, which waspurified by flash chromatography (heptane/EtOAc).

¹H NMR (CDCl₃): δ 1.15-1.95 (m, 12H), 2.10-2.42 (m, 2H), 2.45-2.80 (m,4H), 3.92-4.02 (m, 1H), 4.18-4.36 (m, 2H), 6.75-6.90 (m, 4H).

Example 491-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidethyl ester

To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (3.0 g, 13.09mmol) and ethyl nipecotate (2.65 ml, 17.02 mmol) in DMF (15 ml) wasadded DIPEA (7.5 ml). The reaction mixture was irradiated in themicrowave reactor at 110° C. for 3 min. Water (20 ml) was then added.The reaction mixture was extracted with DCM (3×20 ml). The combinedorganic phases were dried over Na₂SO₄, filtered and evaporated to givethe crude title compound, which was purified by column chromatography(DCM/MeOH, 95:5).

¹H NMR (DMSO-d₆): δ 1.14 (t, 3H), 1.14-1.46 (m, 5H), 2.10-2.80 (m, 6H),3.94 (m, 1H), 4.05 (m, 2H), 4.28 (m, 2H), 6.82 (m, 4H).

Example 50[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol

To a suspension of LiAlH₄ (0.11 g, 2.78 mmol) in dry THF (1 ml) wasadded 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylicacid ethyl ester (0.17 g, 0.55 mmol) in dry THF (10 ml). The reactionmixture was refluxed for 2 h. Water was slowly added under cooling andthe reaction mixture was extracted with EtOAc (3×20 ml). The combinedorganic phases were dried (Na₂SO₄), filtered and the filtrate wasevaporated to give the title compound.

¹H NMR (DMSO-d₆): δ 0.90 (m, 1H), 1.48 (m, 1H), 1.64 (m, 3H), 1.70-2.20(m, 3H), 2.80 (m, 2H), 3.20 (m, 3H), 3.95 (dd, 1H), 4.30 (m, 2H), 4.36(m, 1H), 6.82 (m, 4H).

Example 511-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester

To a solution of1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidethyl ester (10.05 g, 32.90 mmol) in dry THF (100 ml) at −78° C. wasslowly added LDA (20.1 ml, 1.8 M). The reaction mixture was stirred atthis temperature for 1 h. Methyl iodide (2.25 ml, 36.21 mmol) was thenadded, the cooling bath removed and stirring was continued for 10 h.After addition of water, the reaction mixture was extracted with EtOAc(3×25 ml). The combined organic phases were dried over Na₂SO₄, filteredand the filtrate was evaporated to give the title compound, which waspurified by column chromatography (EtOAc/heptane, 70:30).

¹H NMR (DMSO-d₆): δ 1.06 (s, 3H), 1.15 (t, 3H), 1.58 (m, 2H), 1.94 (m,1H), 2.10 (m, 2H), 2.40-2.70 (m, 4H), 3.01 (dd, 1H) 3.94-4.05 (m, 3H),4.28 (m, 2H), 6.85 (m, 4H).

Example 521-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylicacid ethyl ester

Prepared according to the procedure described above for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester except that ethyl iodide was used instead of methyliodide.

¹H NMR (DMSO-d₆): δ 0.74 (t, 3H), 1.04 (m, 1H), 1.10-1.20 (m, 3H), L38(m, 1H), 1.48-1.62 (m, 3H), 1.90-2.02 (m, 3H), 2.40-2.82 (m, 3H), 3.05(m 1H), 3.80-4.12 (m, 3H), 4.20-4.32 (m, 2H), 6.82 (m, 4H).

Example 53[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol

To a suspension of LiAlH₄ (0.59 g, 15.54 mmol) in dry THF (45 ml), wasadded1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester (1.0 g, 3.13 mmol) in dry THF (5 ml). The reactionmixture was refluxed for 1 h. Water was slowly added and the reactionmixture was extracted with EtOAc (3×20 ml). The combined organic phaseswere dried over Na₂SO₄, filtered and the filtrate was evaporated to givethe desired product which, was purified by column chromatography(EtOAc/heptane, 50:50).

¹H NMR (DMSO-d₆): δ 0.85 (s, 3H), 1.06 (m, 1H), 1.31 (m, 1H), 1.50 (m,2H), 1.85-2.45 (m, 6H), 3.22 (m, 2H), 3.95 (m, 1H), 4.30 (m, 2H), 4.40(m, 1H), 6.86 (m, 4H).

Example 541-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine

A solution of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol(0.1 g, 0.36 mmol) in THF (5 ml) was added to NaH (60% in oil, 79.0 mg,1.79 mmol) which was previously washed with heptane. The reactionmixture was stirred at 70° C. for 1 h and then cooled to RT followed bydropwise addition of a solution of methyl iodide (0.034 ml, 0.54 mmol)in THF (1 ml). Stirring was continued for 1 h. Water was slowly addedand the reaction mixture extracted with DCM (3×20 ml). The combinedorganic phases were dried over Na₂SO₄, filtered and the filtrate wasevaporated to give the title compound, which was purified by columnchromatography (DCM/MeOH, 90:10).

¹H NMR (DMSO-d₆): δ 0.88 (s, 3H), 1.08 (m, 1H), 1.35 (m, 1H), 1.49 (m,2H), 1.85-2.45 (m, 6H), 3.15 (m, 2H), 3.31 (s, 3H), 3.95 (m, 1H), 4.27(m, 2H), 6.86 (m, 4H).

Example 551-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethyl-3-methylpiperidine

Prepared according to the procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidineexcept that ethyl iodide was used instead of methyl iodide.

¹H NMR (DMSO-d₆): δ 0.88 (s, 3H), 1.08 (m, 3H), 1.35 (m, 1H), 1.52 (m,2H), 1.85-2.45 (m, 4H), 3.15 (m, 2H), 3.31 (s, 3H), 3.40 (m, 2H), 3.95(m, 1H), 4.28 (m, 2H), 6.86 (m, 4H).

Example 563-Chloromethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine

A mixture of phosphorus oxychloride (1.93 ml, 0.02 mmol) and[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol(0.2 g, 0.72 mmol) was refluxed for 3 h. Excess of phosphorusoxychloride was evaporated. Water was slowly added and the reactionmixture was made alkaline with aq NaOH and extracted with DCM (3×5 ml).The combined organic phases were dried over Na₂SO₄, filtered and thefiltrate was evaporated to give the title compound, which was purifiedby column chromatography (DCM/MeOH, 90:10).

¹H NMR (DMSO-d₆): δ 0.93 (s, 3H), 1.19 (m, 1H), 1.50 (m, 3H), 1.85-2.45(m, 6H), 3.66 (m, 2H), 3.95 (m, 1H), 4.31 (m, 2H), 6.83 (m, 4H).

Example 572-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol

To a solution of1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester (1.13 g, 3.53 mmol) in dry THF (50 ml) under nitrogenat 0° C. a solution of methyl magnesium chloride in THF (3.53 ml, 3.0 M)was added dropwise. The resulting solution was refluxed for 2.5 h. Waterwas then slowly added under cooling and the product was extracted withDCM and purified by column chromatography (DCM/MeOH, 95:5) to give thetitle compound.

¹H NMR (DMSO-d₆): δ 0.94 (s, 3H), 1.04 (d, 6H), 1.24 (m, 1H), 1.50 (m,2H), 1.70-2.48 (m, 7H), 2.52 (br d, 1H), 3.97 (m, 1H), 4.31 (m, 2H),6.82 (m, 4H).

Example 581-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(1-methoxy-1-methylethyl)-3-methylpiperidine

Prepared according to the procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidineexcept that2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-olwas used instead of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol.

¹H NMR (DMSO-d₆): δ 0.90-1.05 (m, 9H), 1.08-2.50 (m, 9H), 2.56 (br d,1H), 3.09 (s, 3H), 3.97 (m, 1H), 4.28 (m, 2H), 6.83 (m, 4H).

Example 591-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-hydroxymethyl-3-methylpiperidin-4-ol

To a mixture of 2,3-dihydrobenzo[1,4]dioxine-2-carbonyl chloride (2.0 g,10.0 mmol) and 4-oxopiperidine-3-carboxylic acid methyl ester (2.14 g,11.0 mmol) in DMF (5 ml) was added triethylamine (1.54 ml). The reactionmixture was stirred at RT for 5 h. The reaction mixture was taken up inwater, made alkaline with aq NaOH and extracted with DCM to give1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-4-oxopiperidine-3-carboxylicacid methyl ester. A mixture of this product (0.2 g, 0.62 mmol), K₂CO₃(0.17 g, 1.23 mmol) and methyl iodide (0.08 ml, 1.25 mmol) in acetone(20 ml) was irradiated in the microwave reactor at 56° C. for 90 min.Water was added and the reaction mixture extracted with EtOAc (3×5 ml).The combined organic phases were dried over Na₂SO₄, filtered and thefiltrate was evaporated to give1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methyl-4-oxopiperidine-3-carboxylicacid methyl ester, which was finally reduced with LiAlH₄ in THF toafford the title compound.

¹H NMR (DMSO-d₆): δ 0.88 (s, 3H), 1.06 (m, 1H), 1.15-3.80 (m, 11H), 3.95(m, 1H), 4.32 (m, 2H), 4.42 (m, 1H), 6.84 (m, 4H).

Example 60 Acetic acid1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester

To a solution of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol(0.5 g, 1.80 mmol), pyridine (0.29 ml) and DCM (40 ml) at 0° C. wasadded acetic anhydride (0.34 ml). The reaction mixture was stirred at RTfor 6 h. Water was slowly added and the reaction mixture extracted withDCM (3×20 ml). The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was evaporated to give the title compound.

¹H NMR (DMSO-d₆): δ 0.85 (s, 3H), 1.08 (m, 1H), 1.33 (m, 1H), 1.50 (m,2H), 1.85-2.45 (m, 7H), 2.49 (s, 3H), 3.95 (m, 1H), 4.25-4.39 (m, 3H),6.83 (m, 4H).

Example 61 Methanesulfonic acid1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester

To a solution of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol(0.92 g, 3.31 mmol) in DCM (40 ml) at 0° C. was added methanesulfonylchloride (0.51 ml). The reaction mixture was stirred at RT for 12 h. Thereaction mixture was made basic with 2 M NaOH and then extracted withDCM (3×20 ml). The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was evaporated to give the title compound.

¹H NMR (DMSO-d₆): δ 0.86 (s, 3H), 0.88-1.40 (m, 5H), 1.50 (m, 2H),2.02-2.32 (m, 5H), 3.16 (m, 3H), 3.96 (m, 1H), 4.29 (m, 2H), 6.81 (m,4H).

Example 62[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol

Prepared according to the procedure described for[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanolexcept that1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-piperidine-3-carboxylicacid ethyl ester was used instead of1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 0.74 (t, 3H), 1.10 (m, 1H), 1.23-1.50 (m, 6H),2.01-2.32 (m, 5H), 3.27 (m, 2H), 3.95 (m, 1H), 4.28 (m, 3H), 6.83 (m,4H).

Example 631-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine

Prepared from[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanolaccording to the procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.

¹H NMR (DMSO-d₆): δ 0.73 (t, 3H), 1.10 (m, 2H), 1.32 (m, 3H), 1.49 (m,2H), 2.01-2.40 (m, 5H), 3.22-3.30 (m, 5H), 3.95 (m, 1H), 4.26 (m, 2H),6.81 (m, 4H).

Example 641-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethoxymethyl-3-methylpiperidine

To a solution of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]methanol(0.20 g, 0.72 mmol) in dry DCM (10 ml) at 0° C. was added DIPEA (0.42ml) and chloromethylmethyl ether (0.11 ml). The reaction mixture wasstirred at RT for 16 h. Water was added and the product was extractedwith DCM (3×20 ml). The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was evaporated to give the title compound.

¹H NMR (DMSO-d₆): δ 0.91 (s, 3H), 1.09 (m, 1H), 1.26 (m, 1H), 1.39 (m,1H), 1.51 (m, 2H), 2.07-2.39 (m, 4H), 3.23-3.32 (m, 6H), 3.95 (m, 1H),4.28 (m, 2H), 4.54 (m, 2H), 6.81 (m, 4H).

Example 651-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone

The procedure described for2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-olwas repeated except that1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylicacid ethyl ester was used as starting material and only one instead ofthree equivalents of methyl magnesium bromide was used.

¹H NMR (DMSO-d₆): δ 0.65 (t, 3H), 0.96 (m, 1H), 1.10-1.80 (m, 5H), 2.05(m, 3H), 2.11 (s, 3H), 2.53 (m, 1H), 2.66 (m, 1H), 3.15 (dd, 1H), 3.93(m, 1H), 4.34 (m, 1H), 4.34 (m, 1H), 6.82 (m, 4H).

Example 661-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanol

To a suspension of LiAlH₄ (0.10 g, 2.58 mmol) in dry THF (4 ml), wasadded1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone(0.08 g, 0.26 mmol) in dry THF (3 ml). The reaction mixture was refluxedfor 1.5 h. Water was slowly added and the reaction mixture extractedwith EtOAc (3×10 ml). The combined organic phases were dried overNa₂SO₄, filtered and the filtrate was evaporated to give the desiredproduct, which was purified by column chromatography (EtOAc/heptane,50:50).

¹H NMR (CDCl₃): δ 0.80 (t, 3H), 1.16 (m, 4H), 1.18-1.90 (m, 5H),1.97-2.27 (m, 3H), 2.25 (m, 2H), 2.94 (m, 2H), 3.97 (m, 2H), 4.31 (m,2H), 6.83 (m, 4H).

Example 673-Allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine

The procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidinewas repeated except that allyl bromide was used instead of methyliodide.

¹H NMR (DMSO-d₆): δ 0.76 (t, 3H), 1.12 (m, 1H), 1.13-1.55 (m, 6H),2.50-2.01 (m, 5H) 3.28 (m, 2H), 3.90 (m, 3H), 4.27 (m, 2H), 5.11 (t,1H), 5.23 (dd, 1H), 5.87 (m, 1H), 6.84 (m, 4H).

Example 682-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol

To a solution of[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol(0.40 g, 1.37 mmol) in DCM (1.5 ml) was added 50% NaOH (6 ml),tetrabutylammonium hydrogensulfate (0.46 g, 1.37 mmol) and tert-butylbromoacetate (5.35 g, 27.45 mmol). The reaction mixture was stirred atRT for 24 h. Water was added, the reaction mixture was extracted withEtOAc (3×10 ml). The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was evaporated to give3-(2-tert-butoxy-ethoxymethyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine.This crude intermediate (0.20 g, 0.50 mmol) in dry THF (2 ml) was thenadded to a suspension of LiAlH₄ (0.19 g, 5.00 mmol) in dry THF (4 ml).The reaction mixture was refluxed for 1.5 h. Water was slowly added andthe reaction mixture was extracted with EtOAc (3×10 ml). The combinedorganic phases were dried over Na₂SO₄, filtered and the filtrate wasevaporated to give the crude product, which was purified by columnchromatography (EtOAc/heptane, 50:50).

¹H NMR (DMSO-d₆): δ 0.76 (t, 3H), 1.10 (m, 1H), 1.23 (br. s, 2H), 1.34(m, 3H), 1.48 (m, 2H), 1.80-2.40 (m, 4H), 3.28 (m, 2H), 3.38 (m, 2H),3.47 (m, 2H), 3.95 (m, 1H), 4.27 (m, 2H), 4.46 (m, 1H), 6.81 (m, 4H).

Example 693-Allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine

The procedure described above for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidinewas repeated except that allyl bromide was used instead of methyliodide.

¹H NMR (CDCl₃): δ 0.95 (s, 3H), 1.12 (m, 1H), 1.42 (m, 1H), 1.55 (m,3H), 2.05-2.62 (m, 7H), 3.21-3.32 (m, 2H), 4.00 (m, 1H), 4.31 (m, 1H),4.35 (m, 1H), 5.14 (d, 1H), 5.25 (d, 1H), 5.90 (m, 1H), 6.83 (m, 4H).

Example 703-Allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylicacid ethyl ester

The procedure described above for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylicacid ethyl ester was repeated except that allyl bromide was used insteadof methyl iodide.

¹H NMR (DMSO-d₆): δ 1.13 (t, 3H), 1.40-2.58 (m, 11H), 3.03 (dd, 1H),3.96 (m, 2H), 4.04 (m, 1H), 4.26 (m, 2H), 5.03 (m, 2H), 5.62 (m, 1H),6.78 (m, 4H).

Example 71[3-Allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol

Prepared from3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylicacid ethyl ester using the procedure described for[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol.

¹H NMR (DMSO-d₆): δ 1.12-1.30 (m, 2H), 1.51 (m, 2H), 2.01-2.45 (m, 7H),3.26 (m, 3H), 3.95 (m, 1H), 4.29 (m, 2H), 4.41 (m, 1H), 4.99 (s, 1H),5.02 (d, 1H), 5.81 (m, 1H), 6.81 (m, 4H).

Example 723-Allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethylpiperidine

Prepared from[3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]methanolusing the procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.

¹H NMR (DMSO-d₆): δ 1.15-1.52 (m, 5H), 1.98-2.50 (m, 6H), 3.10 (m, 2H),3.26 (m, 3H), 3.30 (m, 1H), 3.95 (m, 1H), 4.27 (m, 2H), 5.00 (br d, 1H),5.02 (m, 1H), 5.79 (m, 1H), 6.81 (m, 4H).

Example 733-Allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethylpiperidine

The procedure described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidinewas repeated except that ethyl iodide was used instead of methyl iodide.

¹H NMR (CDCl₃): δ 1.16 (t, 3H), 1.18-1.77 (m, 3H), 1.90-2.88 (m, 8H),3.24 (m, 1H), 3.42 (q, 2H), 3.63 (m, 2H), 3.98 (m, 1H), 4.28 (m, 2H),5.03 (m, 2H), 5.78 (m, 1H), 6.84 (m, 4H).

Example 741-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluoroethoxymethyl)-piperidine

A mixture of methanesulfonic acid1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester (0.35 g, 0.98 mmol), K₂CO₃ (0.68 g) and trifluoroethanol (4 ml)was irradiated in a microwave reactor at 150° C. for 10 min. Water wasadded and the reaction mixture was extracted with DCM (2×20 ml). Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was evaporated to give the title compound, which was purifiedby column chromatography (DCM/MeOH, 90:10).

¹H NMR (DMSO-d₆): δ 0.89 (m, 3H), 1.10 (m, 1H), 1.25-1.60 (m, 4H),2.01-2.50 (m, 4H), 3.39 (m, 1H), 3.48 (m, 2H), 3.80-4.10 (m, 3H), 4.28(m, 2H), 6.81 (m, 4H).

Example 75 2-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethoxy]ethanol

Prepared from[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanolusing the procedure described above for2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.16 (m, 1H), 1.40 (m, 1H), 1.59 (m,2H), 2.16 (d, 1H), 2.30 (br. s, 1H), 2.46 (d, 1H), 2.47-2.50 (m, 3H),3.26 (d, 1H), 3.39 (dd, 1H), 3.45 (d, 1H), 3.52 (m, 2H), 3.70 (m, 2H),4.29 (m, 2H), 6.83 (m, 4H).

Example 76[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]acetic acidethyl ester

To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (1.34 g, 5.84mmol), piperidin-3-yl-acetic acid ethyl ester (1.0 g, 5.84 mmol) inacetonitrile (25 ml) was added K₂CO₃ (0.81 g, 5.84 mmol) and KI (0.97 g,5.84 mmol). The reaction mixture was irradiated under microwaves at 82°C. for 8 h. Water (100 ml) was then added. The reaction mixture wasextracted with DCM (3×50 ml). The combined organic phases were dried(Na₂SO₄), filtered and the filtrate was evaporated to give the titlecompound, which was purified by column chromatography (DCM/MeOH, 95:5).

¹H NMR (DMSO-d₆): δ 0.83 (m, 1H), 1.16 (t, 3H), 1.18-1.59 (m, 3H),1.80-2.40 (m, 5H), 2.52 (m, 2H), 2.79 (m, 2H), 3.93 (dd, 1H), 4.04 (q,2H), 4.29 (m, 2H), 6.81 (m, 4H).

Example 772-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol

To a suspension of LiAlH₄ (0.12 g, 3.16 mmol) in dry THF (4 ml) wasadded [1-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)piperidin-3-yl]aceticacid ethyl ester 2.0 g (0.62 mmol) in dry THF (2 ml). The reactionmixture was refluxed for 1.5 h. Water was slowly added and the reactionmixture was extracted with EtOAc (3×20 ml). The combined organic phaseswere dried (Na₂SO₄), filtered and the filtrate was evaporated to givethe desired product which was purified by column chromatography(EtOAc/heptane, 50:50).

¹H NMR (DMSO-d₆): δ 0.84 (m, 1H), 1.14-2.03 (m, 8H), 2.52 (m, 2H),2.74-2.87 (m, 2H), 3.42 (m, 2H), 3.94 (dd, 1H), 4.29 (m, 3H), 6.81 (m,4H).

Example 781-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyethyl)piperidine

A solution of2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol (0.1g, 0.36 mmol) in THF (5 ml) was added NaH (79.0 mg, 1.79 mmol), whichwas previously washed with heptane. The reaction mixture was stirred at70° C. for 1 h followed by a dropwise addition of a solution ofiodomethane (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continuedfor 1 h. Water was slowly added and the reaction mixture was extractedwith DCM (3×20 ml). The combined organic phases were dried (Na₂SO₄),filtered and the filtrate was evaporated to give the title compound,which was purified by column chromatography (DCM/MeOH, 90:10).

¹H NMR (DMSO-d₆): δ 0.84 (m, 1H), 1.32-2.13 (m, 9H), 2.74-2.83 (m, 2H),3.19 (s, 3H), 3.32 (m, 3H), 3.94 (dd, 1H), 4.29 (m, 2H), 6.83 (m, 4H).

Example 791-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidamide

To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.87mmol) and piperidine-3-carboxylic acid amide (0.13 g, 1.05 mmol) inacetonitrile (20 ml) was added K₂CO₃ (0.60 g, 4.36 mmol) and KI (0.72 g,4.36 mmol). The reaction mixture was refluxed for 2 h. Water (100 ml)was then added. The reaction mixture was extracted with EtOAc (3×5 ml).The combined organic phases were dried (Na₂SO₄), filtered and thefiltrate was evaporated to give the title compound, which was purifiedby column chromatography (EtOAc/heptane, 50:50).

¹H NMR (DMSO-d₆): δ 1.40-1.80 (m, 4H), 1.80-2.40 (m, 3H), 2.50-2.80 (m,4H), 3.94 (m, 1H), 4.30 (m, 2H), 6.83 (m, 4H), 7.31 (s, 2H).

Example 801-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carbonitrile

Thionyl chloride (20 ml) was added under cooling to1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acidamide (2.34 g, 8.46 mmol). The reaction mixture was refluxed for 3 h.Excess of thionyl chloride was evaporated. Water was slowly added to theresidue, the mixture was made alkaline with aq NaOH and extracted withDCM (3×5 ml). The combined organic phases were dried (Na₂SO₄), filteredand the filtrate was evaporated to give the title compound, which waspurified by column chromatography (DCM/MeOH, 90:10).

¹H NMR (DMSO-d₆): δ 1.20 (m, 1H), 1.40-1.70 (m, 5H), 2.50-2.62 (m, 5H),3.98 (m, 1H), 4.32 (m, 2H), 6.82 (m, 4H).

Example 81C-[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methylamine

To a suspension of LiAlH₄ (0.62 g, 16.30 mmol) in dry THF (15 ml) wasadded 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylicacid amide (0.45 g, 01.63 mmol) in dry THF (5 ml). The reaction mixturewas heated under microwaves at 66° C. for 1 h. Water was slowly addedand the mixture extracted with EtOAc (3×20 ml). The combined organicphases were dried (Na₂SO₄), filtered and the filtrate was evaporated togive the desired product, which was purified by column chromatography(DCM/MeOH, 98:2).

¹H NMR (DMSO-d₆): δ 0.84 (m, 1H), 1.40-1.80 (m, 7H), 2.01 (m, 1H), 2.33(m, 2H), 2.70-2.90 (m, 3H), 3.30 (br. s, 1H), 3.94 (m, 1H), 4.28 (m,2H), 6.83 (m, 4H).

Example 82 1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-ol

A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (2.26 g, 9.88mmol), piperidin-3-ol (1.0 g, 9.88 mmol) and K₂CO₃ (6.8 g, 49.43 mmol)in DMF (30 ml) was heated under microwaves at 153° C. for 120 min togive the crude title compound after the usual work-up. The product waspurified by column chromatography (DCM/MeOH, 98:2).

¹H NMR (DMSO-d₆): δ 1.04 (m, 1H), 1.38 (m, 1H), 1.41 (m, 1H), 1.59 (m,1H), 1.60-2.10 (m, 3H), 2.40-2.90 (m, 3H), 3.45 (br. s, 1H), 3.93 (m,1H), 4.29 (m, 2H), 4.61 (m, 1H), 6.82 (m, 4H).

Example 832-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline-8-carboxylicacid methyl ester

To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.88mmol) and 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester(0.14 g, 0.88 mmol) in DMF (10 ml) was added K₂CO₃ (0.61 g, 4.41 mmol).The reaction mixture was heated under microwaves at 140° C. for 10 min.Water was then added and the mixture extracted with DCM (3×5 ml). Thecombined organic phases were dried (Na₂SO₄), filtered and the filtratewas evaporated to give the title compound, which was purified by columnchromatography (DCM/MeOH, 95:5).

¹H NMR (DMSO-d₆): δ 2.70-2.90 (m, 6H), 3.62 (s, 2H), 3.89 (s, 3H), 3.92(m, 1H), 4.28 (m, 2H), 6.85 (m, 4H), 7.01 (d, 1H), 7.11 (t, 1H), 7.18(d, 1H).

Example 84[2-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]methanol

To a suspension of LiAlH₄ (0.20 g, 5.44 mmol) in dry THF (10 ml) wasadded2-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid methyl ester (0.18 g, 0.54 mmol). The reaction mixture was heatedunder microwaves at 80° C. for 10 min. Water (10 ml) was slowly addedunder cooling followed by extraction with EtOAc (3×5 ml). The combinedorganic phases were dried (Na₂SO₄), filtered and the filtrate wasevaporated to give the title compound, which was purified by columnchromatography (EtOAc/heptane, 50:50).

¹H NMR (DMSO-d_(o)): δ 2.70-2.90 (m, 6H), 3.66 (m, 2H), 4.00 (dd, 1H),4.38 (dd, 1H), 4.42 (d, 2H), 4.44 (q, 1H), 5.01 (t, 1H), 6.84 (m, 4H),7.01 (d, 1H), 7.10 (t, 1H), 7.16 (d, 1H).

Example 85(S)-1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylicacid ethyl ester 3-Methylpiperidine-3-carboxylic acid ethyl ester

Ethyl-5-chloro-2-cyano-2-methylpentanoate (DE 31 39 301 A1) (10.43 g,51.2 mmol), PtO₂ hydrate (1.16 g) and concentrated HCl (12.5 ml) inabsolute EtOH (125 ml) were stirred and heated at 40° C. under hydrogenat normal pressure for 2 h. The cooled solution was filtered. Afterevaporation of the solvent, the residue was dissolved in absolute EtOH(125 ml). The solution was cooled with an ice-water bath andtriethylamine (9.8 g, 96.8 mmol) was added. After the addition themixture was stirred at RT for 16 h under nitrogen atmosphere. Thesolvent and triethylamine were evaporated, and the residue was dissolvedin DCM (100 ml) and extracted with 1 M HCl (3×100 ml). After separatingthe layers, ice (150 g) and 5 M NaOH (100 ml) were added to the aqueouslayer, which was then extracted with DCM (3×60 ml). The combinedextracts were dried, filtered and evaporated to dryness followed byvacuum distillation (bp. 62-65° C./2 mbar) to give 6.0 g of the titlecompound as a colorless liquid.

¹H NMR (CDCl₃): δ 1.09 (s, 3H), 1.27 (t, 3H), 1.33-1.57 (m, 4H), 2.17(m, 1H), 2.41 (d, 1H), 2.58 (m, 1H), 2.92 (m, 1H), 3.32 (dd, 1H), 4.17(m, 2H).

(S)-3-methyl-piperidine-3-carboxylic acid ethyl ester

The title compound was resolved from the above racemate according to themethod described in Org. Lett., 7 (2005) 55.

(S)-1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylicacid ethyl ester

(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (6.05 g, 30.5 mmol)in DCM (20 ml) was added to a stirred mixture of(S)-3-methyl-piperidine-3-carboxylic acid ethyl ester (5.0 g, 29.2mmol), DIPEA (5.5 ml, 31.7 mmol) and DCM (30 ml), previously cooled downto 5° C. The cooling bath was removed and stirring continued at RT for 1h. The reaction mixture was washed twice with 1 M HCl, twice with sat.aq NaHCO₃ and twice with water and dried with Na₂SO₄. Solvent wasevaporated to give 9.66 g of the title compound.

¹H NMR (DMSO-d₆): δ 1.05-1.75 (m, 9H), 1.85-2.15 (m, 1H), 2.75-3.18 (m,1H), 3.35-3.78 (m, 2H), 3.95-4.25 (m, 4H), 4.25-4.37 (m, 1H), 5.15-5.50(m, 1H), 6.75-6.95 (m, 4H).

Example 86 Lithium(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylate

(S)-1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylicacid ethyl ester (512 mg, 1.60 mmol), 1 M lithium hydroxide (4.81 ml,4.81 mmol) and THF:H₂O solution (9:1) (5 ml) were heated undermicrowaves at 100° C. for 26 h. The mixture was filtered and evaporatedto dryness. The residue was dissolved in water and washed twice withEtOAc and the aqueous phase was evaporated to dryness to give 353 mg ofthe title compound.

¹H NMR (DMSO-d₆): δ 0.98 (s, 3H), 1.06-1.16 (m, 1H), 1.40-1.49 (m, 1H),1.50-1.61 (m, 1H), 1.69-1.79 (m, 1H), 2.09-2.18 (m, 1H), 2.21-2.30 (m,1H), 2.37-2.50 (m, 3H), 2.60-2.69 (m, 1H), 3.96-4.03 (m, 1H), 4.18-4.26(m, 1H), 4.30-4.37 (dd, 1H, J=2.4, 11.2 Hz), 6.76-6.86 (m, 4H).

Example 87{(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol

A mixture of(S)-1-((R)-2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylicacid ethyl ester (27.7 g, 83.1 mmol) and THF (150 ml) was added to acooled (0° C.) mixture of dry THF (150 ml) and LiAlH₄ (10 g, 264 mmol).The reaction mixture was refluxed for 2 h, after which it was cooled toRT and water was added. The mixture was extracted twice with EtOAc anddried with Na₂SO₄. Solvent was evaporated to give 21.93 g of the titlecompound.

¹H NMR (CD₃OD): δ 0.93 (s, 3H), δ 1.14-1.21 (m, 1H), 1.42-1.48 (m, 1H),1.61-1.69 (m, 2H), 2.22-2.27 (m, 1H), 2.32-2.42 (m, 2H), 2.49-2.60 (m,3H), 3.40-3.47 (m, 2H), 3.92-3.97 (m, 1H), 4.23-4.31 (m, 2H), 6.76-6.82(m, 4H).

Example 882-{(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol

A mixture of{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}-methanol(5.12 g, 18.5 mmol), 50% NaOH (125 ml) and tetrabutylammonium bromide(0.585 g, 1.8 mmol) was stirred at RT for 15 min and then heated up to60° C. 2-(2-Bromoethoxy)tetrahydropyran (11.3 g, 54.0 mmol) was added tothe reaction mixture at 60° C. during 2 h. After the addition thereaction mixture was stirred at 60° C. for 5 h. The reaction mixture wascooled down to RT and brine and water was added. The reaction mixturewas extracted three times with toluene. The toluene phases were combinedand washed twice with water and once with brine, dried (Na₂SO₄) andevaporated to give(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-[2-(tetra-hydropyran-2-yloxy)ethoxymethyl]piperidine.To remove the THP group, this compound was stirred in water (100 ml) andconc. HCl (10 ml) at RT for 3 h. The reaction mixture was washed twicewith toluene and pH of the water phase was adjusted to 11-12 with NaOH.The alkaline phase was extracted twice with toluene. The combinedextracts were washed twice with water and once with brine and dried(Na₂SO₄). Toluene was evaporated and EtOAc was added to the residue.EtOAc was evaporated to give 4.74 g of the crude title compound. Amixture of the crude title compound (4.6 g, 14.3 mmol), EtOAc (50 ml)and (−)-di-p-toluoyl-L-tartaric acid (5.53 g, 14.3 mmol) was stirred at60° C. for 1 hour. The reaction mixture was cooled to RT and stirred fora few hours. The precipitate was filtered, washed with EtOAc and driedunder vacuum at 80° C. The crude product (8.9 g, 12.6 mmol) wasrecrystallized from IPA (90 ml) to give 7.5 g of thedi-p-toluoyl-L-tartrate salt of2-{(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethoxy}ethanol.This salt was stirred in EtOAc (50 ml) and water (50 ml). The pH of themixture was adjusted to 9 (1 M NaOH) and stirring was continued at RTfor 30 min. The phases were separated and the water phase was extractedtwice with EtOAc. The organic layers were combined, dried (Na₂SO₄) andevaporated to give 3.4 g of the pure title compound.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.11-1.18 (m, 1H), 1.39-1.45 (m, 1H),1.56-1.62 (m, 2H), 2.09-2.62 (m, 7H), 3.27-3.29 (d, 1H), 3.44-3.46 (d,1H), 3.51-3.55 (m, 2H), 3.69-3.72 (m, 2H), 3.97-4.02 (m, 1H), 4.24-4.33(m, 2H), 6.80-6.88 (m, 4H).

Example 892-{(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanolD-tartrate

A mixture of2-{(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol(3.1 g, 9.6 mmol) and acetone (30 ml) was heated to 50° C. andD-tartaric acid (1.45 g, 9.7 mmol) was added in small portions at 50° C.The reaction mixture was refluxed for 1 h, after which it was cooleddown to RT and the solvent was evaporated. The residue was dried undervacuum at 40° C. to give 4.17 g of the title salt.

¹H NMR (CDCl₃): δ 0.99 (s, 3H), 1.20-1.32 (m, 1H), 1.52-1.62 (m, 1H),1.68-1.78 (m, 1H), 1.82-1.94 (m, 1H), 2.35-2.60 (m, 2H), 2.78-2.83 (m,1H), 2.90-3.31 (m, 4H), 3.56-3.59 (m, 3H), 3.70-3.74 (m, 2H), 4.02-4.06(m, 1H), 4.27-4.30 (m, 2H), 4.56-4.57 (m, 1H), 6.84-6.88 (m, 4H).

Example 90(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidine

Prepared from{(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}-methanolusing the procedure for preparation of1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidineexcept that 1-bromo-2-methoxyethane was used instead of methyl iodide.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 0.98-1.75 (m, 7H), 2.10-2.60 (m, 5H),3.32-3.34 (m, 1H), 3.36 (s, 3H), 3.56 (m, 3H), 3.98 (dd, 1H), 4.24 (m,1H), 4.35 (m, 1H), 6.83 (m, 4H).

Example 91(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-(2,2,2-trifluoroethoxymethyl)piperidine

Prepared from{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanolas described for1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluoroethoxymethyl)piperidine.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.14 (m, 1H), 1.42 (m, 1H), 1.56 (m,3H), 2.10 (dd, 1H), 2.40 (d, 1H), 2.52 (m, 3H), 3.45 (dd, 1H), 3.53 (t,1H), 3.81 (q, 2H), 3.98 (m, 1H), 4.30 (m, 2H), 6.83 (m, 4H).

Example 92 Methanesulfonic acid(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethylester

A mixture of3-{(R)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(1.05 g, 3.79 mmol) and triethylamine (212 μl, 0.585 g, 5.78 mmol) inDCM was cooled to 0° C. and methanesulfonyl chloride (448 μl, 0.66 g,5.78 mmol) in DCM (1 ml) was added. The mixture was stirred at RT for 2h. The reaction mixture was quenched with water and washed two timeswith sat. aq NaHCO₃. The organic phase was dried (Na₂SO₄) and evaporatedto dryness to give 1.048 g of the title compound.

¹H NMR (CDCl₃): δ 1.02 (s, 3H), 1.15-1.32 (m, 1H), 1.45-1.74 (m, 3H),2.03-2.40 (m, 2H), 2.41-2.83 (m, 4H), 3.00 (s, 3H), 3.93-4.39 (m, 5H),6.80-6.90 (m, 4H).

Example 93 Thioacetic acidS-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl}ester

A mixture of methanesulfonic acid(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethylester (927 mg, 2.61 mmol), thioacetic acid (373 μl, 399 mg, 5.24 mmol)and K₂CO₃ (721 mg, 5.22 mmol) in DMF (35 ml) was heated at 95° C. for 10h. The mixture was evaporated to dryness, dissolved in DCM and washedtwo times with sat. aq NaHCO₃. The organic phase was washed with brine,dried (Na₂SO₄) and evaporated to dryness to give 794 mg of the titlecompound.

¹H NMR (CDCl₃): δ 0.91 (s, 3H), 1.18-1.28 (m, 1H), 1.35-1.45 (m, 1H),1.50-1.67 (m, 2H), 2.01-2.64 (m, 9H), 2.93-3.10 (m, 2H), 3.93-4.02 (m,1H), 4.18-4.38 (m, 2H), 6.78-6.90 (m, 4H).

Example 942-{(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl-sulfanyl}ethanol

Dry MeOH (1 ml) was added to NaOH (35 mg, 0.88 mmol) and the suspensionwas added to an oven dried thioacetic acidS-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl}ester(141 mg, 0.42 mmol) under nitrogen atmosphere. The mixture was stirredat RT for 1 h. 2-Chloroethanol (59 μl, 71 mg, 0.88 mmol) in dry DMF (2ml) was added and the reaction mixture was stirred at RT for 30 min. Themixture was diluted with EtOAc and washed two times with sat. aq NaHCO₃.The combined organic phases were dried (Na₂SO₄) and evaporated todryness. The crude product was purified by flash chromatography using agradient of heptane and EtOAc as eluent to give 17 mg of the titlecompound.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.19-1.29 (m, 2H), 1.41-1.51 (m, 1H),1.53-1.65 (m, 2H), 2.02-2.11 (m, 1H), 2.15-2.25 (m, 1H), 2.48-2.82 (m,8H), 3.67-3.80 (m, 2H), 3.95-4.02 (m, 1H), 4.27-4.34 (m, 2H), 6.79-6.89(m, 4H).

Example 95{(S)-1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}aceticacid tert-butyl ester

To a stirred solution of{(5)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol(0.516 g, 1.8 mmol) in toluene (4 ml) was added tetrabutylammoniumbromide (0.12 g) and 50% NaOH (4 ml). The mixture was stirred at RT for15 min and bromoacetic acid tert-butyl ester (0.53 g) was added. Aftervigorous stirring at RT overnight, the reaction was quenched by additionof brine (15 ml) and the aqueous phase extracted twice with toluene. Thecombined organic phases were extracted with 1 M HCl solution and theacidic water phase was basified by addition of NaOH. Extraction withtoluene and evaporation afforded the title compound (0.48 g) as an oil.

¹H NMR (DMSO-d₆): δ 0.91 (s, 3H), 1.05-1.11 (m, 1H), 1.42 (s, 9H),1.45-1.52 (d, 2H), 2.14 (d, 1H), 2.30 (d, 2H), 2.45-2.54 (m, 4H), 3.31(dd, 2H), 3.90-3.99 (m, 3H), 4.25-4.31 (m, 2H), 6.79-6.86 (m, 4H).

Example 96 Sodium{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl-methoxy}acetate

To a solution of{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}aceticacid tert-butyl ester (0.92 g, 2.11 mmol) in DCM (10 ml) was addedtrifluoroacetic acid (10 ml). The mixture was stirred at RT overnight,after which it was evaporated to dryness. Water was added to the residueand the solution was made basic by addition of aq NaOH. The alkalinewater phase was extracted several times with DCM and the combinedorganic layers were dried with Na₂SO₄ and evaporated. The crude residuewas triturated with IPA to afford the title compound (0.49 g) as a whitesolid.

¹H NMR (DMSO-d₆): δ 0.91 (s, 3H), 1.04-1.09 (m, 1H), 1.36-1.41 (m, 1H),1.52 (m, 2H), 2.20 (s, 2H), 2.36 (s, 2H), 2.48 (m, 3H), 3.18 (d, 1H),3.31 (d, 1H), 3.54 (dd, 2H), 3.95 (dd, 1H), 4.25-4.31 (m, 2H), 6.82-6.84(m, 4H).

Example 972-[(S)-1-((S)-7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol(S)-1-Benzyl-3-methylpiperidine-3-carboxylic acid ethyl ester

(S)-3-Methylpiperidine-3-carboxylic acid ethyl ester (1.16 g, 6.8 mmol),benzyl chloride (0.82 ml, 7.1 mmol), K₂CO₃ (1.22 g, 8.8 mmol) and KI(0.056 g) were stirred and heated in DMF (50 ml) for 2.5 h. The cooledsolution was poured into water and extracted with EtOAc (3×50 ml). Thecombined extracts were washed several times with water and finally withbrine. Drying, filtering and evaporation of the solvent gave 1.64 g ofthe target compound as a yellowish oil.

¹H NMR (CDCl₃): δ 1.12 (s, 3H), 1.23 (t, 3H, J=7 Hz), 1.15-2.15 (m, 6H),2.60 (m, 1H), 2.98 (m, 1H), 3.40 (d, J_(AB)=13.5 Hz, 1H), 3.53 (d,J_(AB)=13.5 Hz, 1H), 4.15 (def q, J=7 Hz, 2H), 7.20-7.40 (m, 5H).

(S)-(1-Benzyl-3-methylpiperidin-3-yl)methanol

(S)-1-Benzyl-3-methylpiperidine-3-carboxylic acid ethyl ester (1.64 g,6.3 mmol) in dry THF (20 ml) was slowly added to a stirred suspension ofLiAlH₄ (0.71 g, 18.8 mmol) in dry THF (20 ml) under nitrogen atmosphere.After the addition the mixture was refluxed for 1.5 h. The solution wascooled with an ice bath, stirred vigorously and 2.5 M NaOH was addedcarefully drop by drop until no reaction occurred and a whiteprecipitate was formed. The solvent was decanted and the solid washedwith EtOAc (2×20 ml). The combined organic phases were dried, filteredand evaporated to dryness to give 1.29 g of the alcohol product as awhite powder.

¹H NMR (CDCl₃): δ 0.74 (s, 3H), 1.20-2.15 (m, 6H), 2.78 (m, 2H), 3.45(s, 2H), 3.56 (d, J_(AB)=10.4 Hz, 1H), 3.61 (d, J_(AB)=10.4 Hz, 1H),5.05 (br s, 1H), 7.23-7.40 (m, 5H).

(S)-1-Benzyl-3-methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine

(S)-(1-Benzyl-3-methylpiperidin-3-yl)methanol (1.29 g, 5.9 mmol) andtetrabutylammonium bromide (0.19 g, 0.59 mmol) were stirred in 50% NaOH(40 ml) for 15 min. The mixture was then heated to 60° C. and2-(2-bromoethoxy)tetrahydropyran (2.7 ml, 17.7 mmol) was slowly added (2h) from a dropping funnel. Stirring was then continued for 4 h at 60° C.Water (40 ml) and brine (20 ml) were added to the cooled mixture, whichwas extracted with toluene (3×50 ml). The combined extracts were washedtwice with water and brine, dried, filtered and evaporated to give 3.0 gof the crude product mixture, which was subjected to flashchromatography on silica. Elution with heptane/EtOAc (80:20) gave 1.14 gof the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 0.95 (s, 3H), 1.16 (m, 1H), 1.45-2.40 (m, 13H),3.25-3.62 (m, 8H), 3.78-3.92 (m, 2H), 4.66 (m, 1H), 7.20-7.36 (m, 5H).The ¹³C NMR spectrum showed several signals duplicated (mixture of THPdiastereomers).

(S)-3-Methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine

(S)-1-Benzyl-3-methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine(1.14 g, 3.3 mmol) in MeOH (11 ml) was added to a suspension of Pd/C(0.23 g) in MeOH (11 ml), followed by ammonium formate (1.03 g, 16.4mmol). The mixture was refluxed for 2 h, after which it was cooled andfiltered through Celite. The catalyst was washed with DCM and thecombined organic phases were evaporated to dryness. To the residue wasadded brine (15 ml) and the solution was extracted with EtOAc (3×30 ml).The extracts were combined, dried, filtered and evaporated to yield 0.71g of the debenzylated product.

¹H NMR (CDCl₃): δ 0.93 (s, 3H), 1.22-1.90 (m, 11H), 2.51 (d, J_(AB)=10.4Hz, 1H), 2.74 (d, J_(AB)=10.4 Hz, 1H), 2.75 (m, 2H), 3.26 (d, J_(AB)=9.2Hz, 1H), 3.33 (d, J_(AB)=9.2 Hz, 1H), 3.51 (dt, 1H), 3.62 (m, 3H),3.80-3.95 (m, 2H), 4.67 (m, 1H). The ¹³C NMR spectrum showed severalsignals duplicated (mixture of THP diastereomers).

1-((S)-7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-[(S)-2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine

(S)-3-Methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine (100mg, 0.39 mmol), methanesulfonic acid(R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (102 mg,0.39 mmol), K₂CO₃ (59 mg, 0.43 mmol) and KI (3 mg) were refluxed in dryDMF (3 ml) for 5 h. Water was added to the cooled mixture, followed byextraction with EtOAc (3×15 ml). The extracts were washed several timeswith water and finally with brine. After drying and filtering, thesolvent was evaporated to give 143 mg of the crude product. This waschromatographed on silica (heptane/EtOAc, 70:30) to give 39 mg of thetitle compound as a colorless oil.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.10-1.90 (m, 10H), 2.15-2.60 (m, 6H),3.28 (d, J_(AB)=8.8 Hz, 1H), 3.34 (d, J_(AB)=8.8 Hz, 1H), 3.49 (m, 1H),3.60 (m, 3H), 3.75-3.95 (m, 3H), 4.23 (m, 1H), 4.30 (m, 1H), 4.65 (t,J=3.6 Hz, 1H), 6.52 (ddd, J=8.4, 8.4 and 3.2 Hz, 1H), 6.58 (dd, J=9.2and 3.2 Hz, 1H), 6.77 (dd, J=8.4 and 5.2 Hz, 1H).

2-[(S)-1-((S)-7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol

The compound obtained above (39 mg, 0.09 mmol) was stirred in 1 M HCl(0.5 ml) at RT for 2 h. Water (5 ml) was added and the mixture waswashed with toluene (5×5 ml). The aqueous layer was then made basic (pH10) with aq Na₂CO₃ and extracted with EtOAc (4×5 ml). Drying, filteringand evaporation of the solvent yielded 18 mg of the title compound as acolorless oil.

¹H NMR (CDCl₃): δ 0.96 (s, 3H), 1.10-1.65 (m, 4H), 2.05-2.70 (m, 7H),3.27 (d, J_(AB)=8.8 Hz, 1H), 3.46 (d, J_(AB)=8.8 Hz, 1H), 3.54 (m, 2H),3.71 (m, 2H), 3.97 (m, 1H), 4.28 (m, 2H), 6.53 (ddd, J=8.4, 8.4 and 2.8Hz, 1H), 6.60 (dd, J=9.2 and 3.2 Hz, 1H), 6.79 (dd, J=8.8 and 5.2 Hz,1H).

Example 981-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylicacid ethyl ester

To a cold (−78° C.) solution of1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acidethyl ester (300 mg, 0.98 mmol) was added 2 M LDA (0.59 ml, 1.08 mmol).The mixture was stirred for 15 minutes. N-fluorobenzenesulfonimide (341mg, 1.08 mmol) was added and the mixture was stirred for 20 min. Thereaction was quenched with sat. NH₄Cl solution. The solvent wasevaporated and the remaining aqueous mixture was extracted two timeswith EtOAc. The organic layers were pooled, dried, concentrated andabsorbed on silica. Flash chromatography (heptane/EtOAc) gave 160 of thetitle compound as a mixture of diastereomers.

¹H NMR (CDCl₃): δ 1.29-1.33 (m, 3H), 1.62-1.71 (m, 1H), 1.84-2.02 (m,3H), 2.36-2.49 (m, 1H), 2.64-3.08 (m, 5H), 3.94-4.04 (m, 1H), 4.19-4.36(m, 4H), 6.78-6.93 (m, 4H).

Example 99[1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidin-3-yl]methanol

1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylicacid methyl ester (145 mg, 0.45 mmol) was dissolved in dry THF (4 ml),cooled to −20° C. and treated with LiAlH₄ (34 mg, 0.90 mmol) for 3 h.Water (1 ml), 1 M NaOH (1 ml) and again water (1 ml) was added. Themixture was filtrated, concentrated and extracted with DCM three times.The organic layers were pooled and purified by flash chromatography(gradient of DCM/MeOH) to give 103 mg of the title compound.

¹H NMR (CDCl₃): δ 1.56-1.89 (m, 5H), 2.05 (s, br, 1H), 2.45-2.83 (m,6H), 3.65-3.80 (m, 2H), 3.95-4.05 (m, 1H), 4.27-4.36 (m, 2H), 6.81-6.96(m, 4H).

Example 100(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylicacid ethyl ester 1-[5-Fluoro-2-((R)-1-(oxiranylmethoxy)-phenyl]-ethanone

A mixture of 5′-fluoro-2′-hydroxyacetophenone (2.04 g, 13.25 mmol),(2R)-(−)-glycidyl tosylate (2.75 g, 12.05 mmol), potassium carbonate(2.16 g, 15.66 mmol) and N,N-dimethyl formamide (20 ml) was heated to60° C. After 6 hours the reaction mixture was cooled down, water (20 ml)and ethyl acetate (20 ml) were added and the layers were separated.Organic phase was recovered and water layer was extracted twice withethyl acetate. Organic phase and ethyl acetate extracts were combinedand washed twice with water and evaporated to dryness. The crude productwas crystallized from 2-propanol to yield 1.91 g (76%) of the pure titlecompound.

¹H NMR (CDCl₃): δ 2.65 (s, 3H), 2.75-2.77 (m, 1H), 2.93-2.95 (t, 1H),3.37-3.41 (m, 1H), 3.95-4.00 (m, 1H), 4.35-4.39 (m, 1H), 6.91-6.94 (m,1H), 7.12-7.17 (m, 1H), 7.44-7.47 (m, 1H).

Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methylester

3-Chloroperoxybenzoic acid (4.19 g, 17.00 mmol) was added in smallportions to 1-[5-fluoro-2-((R)-1-oxiranylmethoxy)-phenyl]-ethanone (2.55g, 12.13 mmol) in dichloromethane (13 ml) and the reaction mixture wasrefluxed for 24 hours. The cooled reaction mixture was washed twice with10% NaHCO3 solution, once with aq NaOH solution and evaporated todryness. 2M NaOH (10.9 ml, 21.84 mmol) was added to the evaporationresidue and the mixture was heated to reflux for 1 hour. The cooledreaction mixture was extracted with dichloromethane and dichloromethanelayer was evaporated to dryness. p-Toluenesulfonyl chloride (2.78 g,14.56 mmol) was added in small portions to the evaporation residue inpyridine (7.5 ml) and the reaction mixture was stirred at RT. After 4hours 1M HCl (7.5 ml) was added and the mixture was stirred for 1 hourat RT. The reaction mixture was extracted twice with ethyl acetate andthe combined ethyl acetate layers were evaporated to dryness. The crudeproduct was crystallized from 2-propanol to yield 2.58 g (63%) of thepure title compound.

¹H NMR (CDCl₃): δ 2.46 (s, 3H), 3.99-4.04 (m, 1H), 4.17-4.26 (m, 3H),4.37-4.42 (m, 1H), 6.49-6.56 (m, 2H), 6.75-6.78 (m, 1H), 7.34-7.36 (d,2H), 7.78-7.80 (d, 2H).

(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylicacid ethyl ester

A mixture of (S)-ethyl-3-methylpiperidine-3-carboxylate (7.23 g, 42.2mmol), Toluene-4-sulfonic acid(R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl ester (15.0 g, 44.3mmol), potassium carbonate (6.42 g, 46.4 mmol) and N,N-dimethylformamide (50 ml) was heated to 120° C. After 4 hours the reactionmixture was cooled down, water (35 ml) was added and the mixture wasextracted twice with ethyl acetate. The combined ethyl acetate layerswere evaporated to dryness. Toluene (35 ml) was added to the evaporationresidue and the mixture was extracted twice with 1M HCl. The combinedacidic water layers were made basic with aq NaOH. The basic water layerwas extracted twice with ethyl acetate and the combined ethyl acetatelayers were evaporated to dryness to yield 10.8 g (76%) of the titlecompound.

¹H NMR (CDCl₃): δ 1.13 (s, 4H), 1.22-1.25 (t, 3H), 1.55-1.73 (m, 2H),2.04-2.20 (m, 3H), 2.49-2.54 (m, 1H), 2.61-2.72 (m, 2H), 3.03-3.06 (d,1H), 3.93-3.98 (m, 1H), 4.07-4.25 (m, 4H), 6.50-6.60 (m, 2H), 6.76-6.80(m, 1H).

Example 101[(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol

(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylicacid ethyl ester (5.0 g, 14.8 mmol) in tetrahydrofuran (10 ml) was addedcarefully to lithium aluminum hydride (1.125 g, 29.6 mmol) intetrahydrofuran (40 ml) and stirred at RT for 1 hour. 2M NaOH was addedto the reaction mixture until the reaction mixture was basic and allexcess LAH was destroyed. The mixture was filtered and the filtrate wasevaporated to dryness. Toluene (30 ml) was added to the evaporationresidue and the mixture was extracted once with 1M HCl. The acidic waterlayer was washed once with toluene and made basic with aq NaOH. Thebasic water layer was extracted twice with ethyl acetate and thecombined ethyl acetate layers were evaporated to dryness and dried invacuum 50° C. to yield 3.02 g (69%) of the title compound.

¹H NMR (CDCl₃): δ 0.82 (s, 3H), 1.20-1.28 (m, 1H), 1.58-1.64 (m, 2H),1.94-2.04 (m, 1H), 2.14-2.22 (m, 2H), 2.48-2.53 (m, 1H), 2.60-2.81 (m,3H), 3.59 (s, 2H), 3.92-3.97 (m, 1H), 4.23-4.34 (m, 2H), 6.51-6.56 (m,1H), 6.60-6.63 (m, 1H), 6.77-6.80 (m, 1H).

Example 102(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine

[(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol(2.5 g, 8.5 mmol) in tetrahydrofuran (10 ml) was added slowly to amixture of sodium hydride, 60% in oil (1.354 g, 33.9 mmol) andtetrahydrofuran (15 ml). The reaction mixture was heated at 60° C. for 2hours after the mixture was cooled down and iodomethane (0.685 ml, 11.0mmol) in tetrahydrofuran (3 ml) was added. The mixture was stirred at RTfor 1 hour, water (25 ml) was added carefully and the mixture wasextracted twice with ethyl acetate. The combined ethyl acetate layerswere evaporated to dryness. Ethyl acetate (20 ml) was added to theevaporation residue and was made acidic with aq HCl. The layers wereseparated and the water layer was made basic with aq NaOH and extractedtwice with ethyl acetate. The combined ethyl acetate layers wereevaporated to dryness to yield 2.34 g (89%) of the title compound.

¹H NMR (DMSO): δ 0.89 (s, 3H), 1.07-1.11 (m, 1H), 1.32-1.39 (m, 1H),1.49-1.52 (m, 2H), 2.11-2.14 (m, 1H), 2.25-2.32 (m, 2H), 2.43-2.52 (m,3H), 3.14-3.19 (d, 2H), 3.23 (s, 3H), 3.92-3.97 (m, 1H), 4.27-4.31 (m,2H), 6.62-6.67 (m, 1H), 6.71-6.75 (m, 1H), 6.85-6.88 (m, 1H).

Example 103(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine.HCl

Hydrochloride salt was made by using ˜10% 2-Propanol/HCl solution (80ml) which was added slowly to a(S)-1-((S)-7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine(11.2 g, 36.2 mmol) in 2-propanol (30 ml). The title product wascrystallized from 2-propanol to yield 7.7 g (62%) of the pure titlecompound. The filtrate was recovered and recrystallized to yield 2.7 g(22%) of the pure title compound (total yield 84%).

¹H NMR (DMSO): δ 0.91 & 1.19 (s, 3H), 1.26-1.35 (m, 2H), 1.45-1.75 (m,2H), 1.90-1.96 (m, 1H), 2.77-3.02 (m, 2H), 3.09-3.15 (m, 1H), 3.22-3.51(m, 7H), 3.59-3.72 (m, 1H), 4.03-4.07 (m, 1H), 4.30-4.34 (m, 1H),5.00-5.04 & 5.14-5.18 (m, 1H), 6.72-6.77 (m, 1H), 6.81-6.85 (m, 1H),6.92-6.96 (m, 1H), 10.29 & 10.80 (bs, 1H).

Example 104(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]-dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidine

A mixture of{(5)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-yl}methanol(134 mg, 0.48 mmol), tetrabutylammonium bromide (0.031 mg, 0.10 mmol)and 50% NaOH solution (2 ml) in toluene (2 ml) was stirred at roomtemperature for 15 min. Methyl iodide (0.24 ml, 3.86 mmol) was addeddrop wise and the mixture was stirred for 6 h 45 min. Saturated NaCl,water and EtOAc were added and the phases were separated. The aqueousphase was extracted twice with EtOAc and combined organic phases werewashed with water and saturated NaCl. The organic phase was dried(Na₂SO₄), filtered and evaporated to dryness. The crude product waspurified with flash chromatography using gradient of heptane and EtOAcas eluent to give 27 mg of the title compound.

¹H NMR (CDCl₃): δ 0.95 (s, 3H), 1.10-1.30 (m, 2H), 1.35-1.45. (m, 1H),1.56-1.64 (m, 1H), 2.15-2.41 (m, 3H), 2.44-2.54 (m, 2H), 2.56-2.64 (m,1H), 3.15-3.26 (m, 2H), 3.33 (s, 3H), 3.94-4.02 (m, 1H), 4.21-4.29 (m,1H), 4.32-4.38 (m, 1H), 6.79-6.90 (m, 4H).

Example 1053-{(R*)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenylamine

A mixture of trifluoro-methanesulfonic acid3-{(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenylester (1.039 g, 2.27 mmol), cesium carbonate (1.036 g, 3.18 mmol),palladium acetate (0.015, 0.068 mmol),(R)-(±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.064 g, 0.102 mmol)and benzophenone imine (0.457 ml, 2.73 mmol) in dry tetrahydrofuran (6ml) was heated in a microwave reactor at 80° C. for 10 hours. Themixture was filtered and evaporated to dryness. The crude product waspurified by flash chromatography using a gradient of heptane and EtOAcas eluent. The residue on evaporation was dissolved in dry methanol,sodium acetate (0.54 g, 6.55 mmol) and hydroxylamine hydrochloride (0.36g, 5.24 mmol) was added and the mixture was stirred at room temperaturefor 1.5 h. The mixture was evaporated to dryness, dissolved in EtOAc andwashed with 1M Na₂CO₃. The organic layer was dried (Na₂SO₄), filteredand evaporated to dryness. The crude product was purified by flashchromatography using gradient of heptane and EtOAc as eluent to give 151mg of the title compound.

¹H NMR (CDCl₃): δ 1.37-1.50 (m, 1H)1.64-1.81 (m, 2H), 1.79-1.92 (m, 1H),2.09-2.22 (m, 2H), 2.56-2.64 (m, 1H), 2.66-2.77 (m, 2H), 2.89-2.97 (m,1H), 3.10-3.07 (m, 1H), 3.61 (s(broad), 2H), 3.96-4.03 (m, 1H),4.27-4.35 (m, 2H), 6.51-6.58 (m, 2H), 6.61-6.65 (m, 1H), 6.76-6.90 (m,4H), 7.09 (t, 1H).

Example 106(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoloxalate

To a hot solution (70° C.) of(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol(10 g, 30.7 mmol) in dry isopropyl alcohol (75 ml) a heated solution(70° C.) of oxalic acid (2.77 g, 30.7 mmol) in dry isopropyl alcohol (25ml) was added. Precipitation was occurred and the mixture was heated upto 80° C. After one hour stirring it was slowly cooled to roomtemperature and stirred over night. The mixture was cooled to 0° C.,stirred for two hours and the precipitate was filtered to give 11.76 gof the desired salt.

¹H NMR (MeOD): δ 1.73-1.82 (m, 1H), 1.93-2.10 (m, 3H), 3.05-3.24 (m,3H), 3.30-3.48 (m, 2H), 3.66-3.73 (m, 2H), 3.99-4.05 (m, 1H), 4.26-4.32(m, 1H), 4.78-4.83 (m, 1H), 6.67-6.77 (m, 3H), 6.82-6.91 (m, 4H), 7.16(t, 1H).

Example 107(S)-2-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol

(S)-4-((2,6-Dimethoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane

A mixture of 2,6-dimethoxyphenol (2.00 g, 12.97 mmol),(R)-(−)-2,2-dimethyl-1,3-dioxalan-4-ylmethyl p-toluenesulfonate (3.72 g,12.97 mmol) and NaH (60% dispersion in mineral oil, 0.86 g, 21.50 mmol)in N,N-dimethylformamide (55 ml) were stirred at +25° C. for 30 min, andat +150° C. for 4.5 h. The reaction mixture was cooled down, water (50ml) and diethyl ether (40 ml) were added and the layers were separated.Organic phase was recovered and water layer was extracted twice withdiethyl ether. Organic phase and diethyl ether extracts were combinedand washed five times with water and saturated sodium chloride solution.The combined organic phase was dried (Na₂SO₄), filtered and evaporatedto dryness to give 2.91 g of the title compound.

¹H NMR (CDCl₃): δ 1.38 (s, 3H), 1.43 (s, 3H), 3.82-3.90 (m, 1H), 3.85(s, 6H), 4.02-4.05 (m, 1H), 4.12-4.18 (m, 2H), 4.42-4.48 (m, 1H),6.56-6.58 (d, 2H), 6.97-7.02 (tr, 1H).

(R)-3-(2,6-Dimethoxyphenoxy)propane-1,2-diol

A mixture of(S)-4((2,6-dimethoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (2.91 g,10.85 mmol) and Amberlyst 15® (1.60 g) in methanol (30 ml) were stirredfor 5 d. The mixture was filtered and evaporated to dryness to give 2.26g of the title compound.

¹H NMR (CDCl₃): δ 3.70-3.75 (m, 2H), 3.87 (s, 6H), 3.94-3.96 (m, 2H),4.23-4.25 (m, 1H), 6.58-6.60 (d, 2H), 7.00-7.04 (tr, 1H).

Methanesulfonic acid(S)-3-(2,6-dimethoxy-phenoxy)-2-methanesulfonyloxy-propyl ester

(R)-3-(2,6-Dimethoxyphenoxy)propane-1,2-diol (2.26 g, 9.90 mmol) indichloromethane (20 ml) was cooled to 0° C. and stirred under nitrogenatmosphere. Triethyl amine (2.94 g, 29.00 mmol) was added in 15 min.Methanesulfonic acid chloride (2.61 g, 21.80 mmol) was added, and themixture was stirred at +25° C. for 3 h. Dichloromethane (20 ml) and 1 MNaHSO₄ solution (10 ml) were added and the layers were separated.Organic layer was washed with 1 M NaHSO₄ solution (10 ml), water (10 ml)and saturated sodium chloride solution (10 ml), dried (Na₂SO₄), filteredand evaporated to dryness to give 3.08 g of the title compound.

¹H NMR (CDCl₃): δ 3.10 (s, 3H), 3.18 (s, 3H), 4.20-4.22 (m, 2H), 3.85(s, 6H), 4.56-4.60 (m, 1H), 4.66-4.69 (m, 1H), 5.14-5.16 (m, 1H),6.56-6.59 (d, 2H), 7.01-7.05 (tr, 1H).

Methanesulfonic acid(S)-3-(2,6-dihydroxy-phenoxy)-2-methanesulfonyloxy-propyl ester

Methanesulfonic acid(S)-3-(2,6-dimethoxy-phenoxy)-2-methanesulfonyloxy-propyl ester (3.08 g,8.00 mmol) in) in dichloromethane (40 ml) was cooled to 0° C. andstirred under nitrogen atmosphere. Boron tribromide (1 M solution indichloromethane, 18 ml, 18 mmol) was added in 15 min. The mixture wasstrirred at +25° C. for 4 h, and poured on mixture of ice (10 g) andwater (15 ml), and the layers were separated. Organic phase wasrecovered and water layer was extracted twice with dichloromethane (15ml). Organic phase and dichloromethane extracts were combined and washedwith water (15 ml) and saturated sodium chloride solution (15 ml). Thecombined organic phase was dried (Na₂SO₄), filtered and evaporated todryness to give 2.53 g of the title compound.

¹H NMR (DMSO): δ 3.24 (s, 3H), 3.28 (s, 3H), 4.12-4.14 (m, 2H),4.58-4.60 (m, 2H), 5.14-5.19 (m, 1H), 6.31-6.33 (d, 2H), 6.67-6.71 (tr,1H), 9.20 (s, 3H).

Methanesulfonic acid(R)-5-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester

A mixture of methanesulfonic acid(S)-3-(2,6-dihydroxy-phenoxy)-2-methanesulfonyloxy-propyl ester (253 g,7.10 mmol) and potassium carbonate (1.14 g, 8.30 mmol) in acetone (30ml) was refluxed under nitrogen atmosphere for 3.5 h. The reactionmixture was cooled down, filtered and evaporated to dryness. The crudeproduct was purified with flash chromatography using dichloromethane andethyl acetate as eluents to give 0.75 g of the title compound.

¹H NMR (DMSO): δ 3.24 (s, 3H), 3.99-4.03 (m, 1H), 4.37-4.42 (m, 2H),4.47-4.49 (m, 2H), 6.35-6.41 (m, 2H), 6.61-6.65 (tr, 1H), 9.22 (s, 1H).

Methanesulfonic acid(R)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester

A mixture of methanesulfonic acid(R)-5-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (0.6 g, 1.69mmol), benzyl bromide (0.4 g, 2.30 mmol) and potassium carbonate (1.14g, 8.30 mmol) in acetone (30 ml) was refluxed under nitrogen atmospherefor 5 h. The crude product was crystallized from 2-propanol to yield 8.8mg of the pure title compound.

¹H NMR (CDCl₃): δ 3.06 (s, 3H), 4.11-4.18 (m, 1H), 4.35-4.38 (dd, 1H),4.43-4.46 (m, 2H), 4.47-4.49 (m, 1H), 5.12 (s, 1H), 6.54-6.56 (d, 2H),6.73-6.77 (tr, 1H), 7.30-7.44 (m, 5H).

3-[(R*)-1-((S)-5-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol

A mixture of hydrochloride salt of (R*)-3-(piperidin-3-yl)-phenol (240mg, 1.12 mmol) and sodium bicarbonate in N,N-dimethylformamide (3 ml)were stirred at +120° C. under nitrogen atmosphere. To this mixture, amixture of methanesulfonic acid(R)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (390 mg,1.11 mmol) in N,N-dimethylformamide (3 ml) was added, and stirred at+130° C. for 3.5 h. The reaction mixture was cooled down, water (20 ml)and ethyl acetate (15 ml) were added and the layers were separated.Organic phase was recovered and water layer was extracted twice withethyl acetate. Organic phase and ethyl acetate extracts were combinedand washed five times with water and saturated sodium chloride solution.The combined organic phase was dried (Na₂SO₄), filtered and evaporatedto dryness. The crude product was purified with flash chromatographyusing heptane and ethyl acetate as eluents to give 160 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.42-1.46 (m, 1H), 1.72-1.74 (m, 1H), 1.89-1.93 (m,1H), 2.14-2.19 (q, 2H), 2.63-2.82 (m, 3H), 2.91-2.94 (d, 1H), 3.03-3.06(d, 1H), 4.02-4.06 (m, 1H), 4.31-4.34 (q, 1H), 4.38-4.41 (m, 1H), 5.29(s, 1H), 6.45-6.53 (m, 2H), 6.66-6.72 (m, 3H), 6.79-6.81 (d, 1H),7.14-7.18 (tr, 3H), 7.26-7.44 (m, 5H).

(S)-2-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol

A mixture of3-[(R*)-1-((S)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol(84 mg, 0.19 mmol) and palladium-on-carbon (60 mg) in ethyl acetate (10ml) were stirred and hydrogenated for 6 h. The reaction mixture wasfiltered and washed with ethyl acetate (10 ml), and evaporated todryness. The crude product was purified with flash chromatography usingdichloromethane and methanol as eluents to give 65 mg of the titlecompound.

¹H NMR (CDCl₃): δ 1.40-1.49 (m, 1H), 1.76-1.77 (m, 1H), 1.90-1.93 (m,1H), 2.13-2.23 (m, 2H), 2.60-2.75 (m, 2H), 2.97-3.00 (d, 1H), 3.11-3.13(d, 1H), 3.97-4.02 (m, 1H), 4.32-4.39 (m, 2H), 6.34-6.41 (d, 1H),6.50-6.52 (d, 1H), 6.67-6.72 (m, 5H), 6.77-6.79 (d, 1H), 7.15-7.19 (tr,1H).

Example 1081-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methanol

(R)-2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid (27.9 mmol, 5.02 g)was dissolved in dry THF (30 ml). LiAlH₄ (56.9 mmol, 2.16 g) was added.The mixture was refluxed for 70 minutes. After cooling, the reaction wasquenched with water and 1 M NaOH. The mixture was fitrated throughCelite and evaporated to dryness. This gave 4.3 g of the title compound.

¹H NMR (CDCl₃): δ 3.81-3.95 (m, 2H), 4.09-4.16 (m, 1H), 4.24-4.32 (m,2H), 6.83-6.93 (m, 4H)

Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methylester

(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methanol (24.1 mmol, 4.0 g),triethylamine (24.3 mmol, 3.42 ml) and DCM (50 ml) were mixed andstirred on an ice-bath. p-Toluenesulfonyl chloride (24.3 mmol, 4.63 g)in DCM (10 ml) was added dropwise. The mixture was stirred over night atr.t and washed with water. The organic phase was evaporated to dryness.The crude product was dissolved in THF (10 ml) and treated with 1 M NaOH(2 ml) for 10 minutes. Water (100 ml) was added. The aqueous solutionwas extracted with EtOAc, the organic phase was dried and evaporated todryness. Flash chromatography, using heptane/EtOAc as eluent gave 7.66 gof the desired product.

¹H NMR (DMSO): δ 2.42 (s, 3H), 3.91-3.99 (m, 1H), 4.17-4.29 (m, 2H),4.31-4.38 (m, 1H), 4.40-4.46 (m, 1H), 6.75-6.86 (m, 4H), 7.48 (d, 2H),7.80 (d, 2H)

1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine

Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methylester (0.156 mmol), 3-(2-methoxyphenyl)pyrrolidine HCl (1.55 mmol, 32mg), K₂CO₃ (0.342 mmol, 47 mg) and acetonitrile (1 ml) were mixed andheated in a microwave reactor at 120 C.° for 2.5 h. The reaction mixturewas filtrated and the solution was absorbed on silica. Flashchromatography, using a gradient of heptane/EtOAc as eluent, gave 20 mgg of the title compound.

¹H NMR (MeOD): δ 1.86-1.97 (m, 1H), 2.55-2.56 (m, 1H), 2.54-2.65 (m,1H), 2.74-2.89 (m, 3H), 2.93-3.06 (m, 1H), 3.11-3.23 (m, 1H), 3.67-3.77(m, 1H), 3.93-4.00 (m, 1H), 4.27-4.37 (m, 2H), 6.77-6.94 (m, 5H),7.14-7.20 (m, 1H), 7.24-7.29 (m, 1H)

Example 109(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-fluoro-ethoxymethyl)-3-methyl-piperidine.HCl

2-{(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethoxy}-ethanol(15.56 mmol, 5.0 g,) was dissolved in DCM (30 ml) under nitrogenprotection. 4 A molecular sieves were added. The mixture was cooled to5° C. and stirred for 5 minutes. Diethylaminosulfur trifluoride (23.33mmol, 3.06 ml) was added. The mixture was stirred at r.t for 4 h. 1 MNa₂CO₃ (50 ml) was added. The phases were separated, the organic phasewas evaporated to dryness. Flash chromatography gave 1.04 g desiredproduct. This crude product was treated with HCl/EtOH and evaporated todryness. The title compound was crystallised (1.02 g) from diethylether.

¹H NMR (DMSO): δ 0.94 (s, 1.5H), 1.19 (s, 1.5H), 1.27-1.39 (m, 1H),1.40-1.54 (m, 0.51-1), 1.61-2.00 (m, 2.5H), 2.78-3.06 (m, 2H), 3.20-3.29(m, 3H), 3.40-3.88 (m, 5H), 3.98-4.12 (m, 1H), 4.27-4.38 (m, 1H),4.46-4.69 (m, 2H), 4.89-5.03 (m, 1H), 6.80-6.96 (m, 4H), 9.78 (s, br,0.5H), 10.34 (s, br, 0.5H)

Example 110(R*)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(3-fluoromethoxy-phenyl)-piperidine(R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluoromethoxy-phenyl)-piperidin-1-yl]-methanone

Bromofluoromethane-pyridinium adduct (excess) was condensed in a vial.(R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-yl]-methanone(1.84 mmol, 0.623 g) and K₂CO₃ (3.67 mmol, 0.507 mmol) were added andthe tube was sealed. Acetonitril (5 ml) was added. The reaction wasstirred at 120° C. for 60 min. After cooling, the mixture was evaporatedto dryness, taken up in DCM and washed with water. The organic phase wasevaporated to dryness. 0.680 g of the title compound was obtained.

¹H NMR (MeOD): δ 1.75-1.98 (m, 3H), 2.63-2.93 (m, 2H), 3.14-3.28 (m,2H), 4.11-4.31 (m, 2H), 4.37-4.46 (m, 1H), 4.51-4.60 (m, 1H), 5.07-5.13(m, 1H), 5.73 (d, 2H), 6.78-7.09 (m, 7H), 7.29 (t, 1H)

(R*)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(3-fluoromethoxy-phenyl)-piperidine

(R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluoromethoxy-phenyl)-piperidin-1-yl]-methanone(0.13 mmol, 50 mg) was treated with BH₃ THF according to the abovegeneral procedure. Flash chromatography gave the title compound.

¹H NMR (CDCl₃): δ 1.37-1.49 (m, 1H), 1.59-1.83 (m, 2H), 1.84-1.96 (m,1H), 2.11-2.24 (m, 2H), 2.56-2.63 (m, 1H), 2.67-2.73 (m, 1H), 2.77-2.86(m, 1H), 2.90-2.98 (m, 1H), 3.01-3.07 (m, 1H), 3.94-4.04 (m, 1H),4.28-4.36 (m, 2H), 5.71 (d, 2H), 6.78-7.04 (m, 7H), 7.22-7.31 (m, 1H)

Example 1111-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylicacid methyl ester1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

The title compound was prepared using 200 mg (1.21 mmol) of2,3-dihydro-benzo[1,4]dioxin-2-ylmethylamine and 0.17 mL (1.21 mmol) ofdimethyl itaconate according to the procedure for substitutedpyrrolidines described in J. Org. Chem. 26 (1961) 1519-1524.Purification by column chromatography (silica gel, heptane/ethylacetate, 1:2) afforded the pure product.

¹H NMR (MeOD, c6055): 2.62-2.73 (m, 2H), 3.33-3.39 (m, 1H), 3.52-3.64(m, 2H), 3.66 (s, 1.5H), 3.74 (s, 1.5H), 3.76-3.96 (m, 3H), 4.26 (dm,1H), 4.34-4.38 (m, 1H), 6.78-6.86 (m, 4H).

1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylicacid methyl ester

A solution containing 300 mg (1.03 mmol) of1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester in dry tetrahydrofuran (4 mL) was cooled to 0° C.under nitrogen. After adding 4 mL of 1M BH₃-tetrahydrofuran solution(4.12 mmol), the reaction mixture was allowed to warm to roomtemperature and it was stirred for 5 h. Decomposition of the boroncomplexes was effected by addition of 3 mL of methanol and 3 mL of 6 MHCl-solution followed by stirring the mixture at 40° C. for ½ h.Tetrahydrofuran was evaporated off under vacuum. The residue wasdissolved in 50 mL of water and the pH of the solution was adjusted to10 using 1M Na₂CO₃ solution. The water phase was extracted with ethylacetate (3×25 mL), and the combined organic phases were dried overanhydrous sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by column chromatography (silica gel, heptane/ethylacetate, 7:3).

¹H NMR (MeOD, c6363): 2.02-2.13 (m, 2H), 2.61-3.12 (m, 7H), 3.68 (s,1.5H), 3.68 (s, 1.5H), 3.91 (dd, 1H), 4.25-4.31 (m, 2H), 6.76-6.85 (m,4H).

Example 112[1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-yl]-methanol

To a solution containing 130 mg (0.45 mmol) of1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester in dry tetrahydrofuran (4 mL) was added 68 mg (1.79mmol) of LiAlH₄. The reaction mixture was stirred at room temperaturefor 2½ h, and subsequently refluxed for 2 h. After the reaction mixturewas cooled to room temperature, it was quenched with water and 1 M NaOH.The solution was filtered through celite and the filtrate was evaporatedto dryness. Purification by column chromatography (silica gel,triethylamine/ethyl acetate, 1:99) afforded the title compound.

¹H NMR (MeOD, c6802): 1.48-1.56 (m, 1H), 1.91-2.01 (m, 1H), 2.31-2.49(m, 2H), 2.57-2.90 (m, 5H), 3.44-3.53 (m, 2H), 3.94 (dd, 1H), 4.26-4.39(m, 2H), 6.77-6.85 (m, 4H).

Example 1132-[1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-ylmethoxy]-ethanol

To a solution containing 50 mg (0.19 mmol) of[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-yl]-methanolin dichloromethane (1.5 mL), 1.5 mL of cold aqueous NaOH-solution (50%,w/w) and 6 mg (0.02 mmol) of tert-butylammonium bromide were added at 0°C. The reaction mixture was stirred for ½ h at 0° C. After adding 28 μL(0.19 mmol) of tert-butylbromoacetate the stirring was continued for 3 hat 10° C. Subsequent addition of water (10 mL) and dichloromethane (40mL) was followed by stirring the mixture for additional 10 min at roomtemperature. The phases were separated, and the organic phase was washedwith 5% NaHCO₃ (1×20 mL), dried over anhydrous sodium sulfate, filtered,and evaporated to dryness. The crude product was dried under high vacuumand redissolved in dry tetrahydrofuran (4 mL) and reduced with 15 mg(0.40 mmol) of LiAlH₄ using the same procedure as above. The crudeproduct was purified by column chromatography (silica gel,methanol/triethylamine/ethyl acetate, 1:1:99).

¹H NMR (MeOD, c6936): 1.49-1.58 (m, 1H), 1.93-2.00 (m, 1H), 2.42-2.90(m, 7H), 3.38-3.46 (m, 2H), 3.51 (t, 2H), 3.65 (t, 2H), 3.91-3.96 (m,1H), 4.26/1.32 (m, 2H), 6.77-6.85 (m, 4H).

Example 1141-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylicacid methyl ester

To a solution containing 80 mg (0.29 mmol) of1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylicacid methyl ester in dry tetrahydrofuran (4.5 mL) at −78° C. undernitrogen was added 0.3 mL (0.58 mmol) of lithium diisopropylamine (2.0 Msolution in heptane/tetrahydrofuran/ethylbenzene). The reaction mixturewas stirred at −78° C. for 1 h and subsequently 0.04 mL (0.58 mmol) ofiodomethane was added. The reaction mixture was allowed to warm to roomtemperature and the stirring was continued for 3 h. The reaction wasquenched with 15 mL of saturated aqueous NH₄Cl-solution and thetetrahydrofuran was evaporated off under vacuum. Water (50 mL) was addedand the pH was adjusted to 10 using 1M Na₂CO₃. The water phase wasextracted with ethyl acetate (3×25 mL), and the combined organic phaseswere dried over anhydrous sodium sulfate, filtered, and evaporated todryness, and the residue was dried under high vacuum.

¹H NMR (MeOD, c6744): 1.34 (s, 3H), 1.64-1.71 (m, 1H), 2.37-2.44 (m,1H), 2.51 (dd, 1H), 2.68-2.83 (m, 4H), 3.17 (dd, 1H), 3.68 (s, 1.5H),3.69 (s, 1.5H), 3.94 (ddd, 1H), 4.24-4.29 (m, 2H), 6.76-6.85 (m, 4H).

Example 115[1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanol

The reduction of 84 mg (0.28 mmol) of1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylicacid methyl ester with 20 mg (0.53 mmol) of LiAlH₄ was performed usingthe procedure described above. Purification by column chromatography(silica gel, methanol/triethylamine/dichloromethane, 1:1:99) yielded thedesired pure alcohol.

¹H NMR (MeOD, c6807): 1.10 (s, 3H), 1.47-1.53 (m, 1H), 1.69-1.77 (m,1H), 2.31 (dd, 1H), 2.60-2.80 (m, 5H), 3.36 (AB d, 1H), 3.38 (AB d, 1H),3.92 (dd, 1H), 4.24-4.29 (m, 2H), 6.73-6.84 (m, 4H).

Example 1162-[1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-ylmethoxyl]-ethanol

38 mg (0.14 mmol) of[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanolwas treated with 21 μL (0.14 mmol) of tert-butylbromoacetate using thesame procedure as described for example 112. Purification by columnchromatography (silica gel, triethylamine/ethyl acetate/heptane,1:10:90) yielded the desired intermediate. The reduction of 30 mg (0.08mmol) of the intermediate was performed with 6 mg (0.16 mmol) of LiAlH₄using the same procedure as described for example 112. Purification bycolumn chromatography (silica gel, triethylamine/ethyl acetate, 1:99)yielded the desired pure alcohol.

¹H NMR (MeOD): 1.13 (s, 3H), 1.47-1.54 (m, 1H), 1.75-1.82 (m, 1H), 2.34(dd, 1H), 2.64-2.79 (m, 5H), 3.27 (AB d, 1H), 3.32 (AB d, 1H), 3.52 (t,1H), 3.52 (t, 1H), 3.66 (t, 2H), 3.67 (t, 1H), 3.93 (dd, 1H), 4.25-4.30(m, 2H), 6.76-6.85 (m, 4H).

Example 1171-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-pyrrolidine

A solution of 56 mg (0.21 mmol) of[1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanolin 1.5 ml of tetrahydrofuran was added to a flask containing 58 mg (2.40mmol) of sodium hydride, previously washed with heptane under argon. Thereaction mixture was stirred at 60° C. for 2 h, cooled to 0° C. followedby dropwise addition of a solution containing 16 μl (0.25 mmol) ofiodomethane in tetrahydrofuran (0.5 ml). The reaction mixture wasallowed to warm to room temperature and the stirring was continued for1½ h. Water was slowly added and tetrahydrofuran was evaporated off andthe water phase was extracted with dichloromethane (3×25 ml). Thecombined organic phases were dried over anhydrous sodium sulfate,filtered, and evaporated to dryness. Purification by columnchromatography (silica gel, ethyl acetate/heptane, 7:13) yielded thedesired pure methyl ether.

¹H NMR (MeOD, c9843): 1.11 (s, 3H), 1.46-1.53 (m, 1H), 1.69-1.76 (m,1H), 2.34 (dd, 1H), 2.55-2.74 (m, 5H), 3.16-3.23 (m, 2H), 3.33 (s,1.5H), 3.34 (s, 1.5H), 3.93 (dd, 1H), 4.21-4.30 (m, 2H), 6.78-6.84 (m,4H).

Example 1183-[(R)-1-((S)-7-Nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol(S)-2-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol

4-Nitrobenzene-1,2-diol (12, 9 mmol, 2.0 g) was dissolved in dry DMF (15ml). Anhydrous potassium carbonate (15.5 mmol, 2.1 g) was added andreaction mixture was warmed to 50° C. (2R)-(−)-glycidyl tosylate (13, 5mmol, 3.2 g) was dissolved to DMF (2 ml) and added drop wise at 50° C.The reaction mixture was heated to 120° C. for 2 h. After cooling themixture was quenched with water and filtered. The water layer wasextracted twice with ethyl acetate. The organic phases were combined andwashed twice with water and saturated sodium chloride solution. Theorganic phase was dried (Na₂SO₄), filtered and evaporated to dryness.This gave 2.1 g of the title compound as a mixture of isomers (20/80).Purification was done by crystallizations (CHCl₃ and chlorobenzen) togive 0.6 g of the title compound.

¹H NMR (DMSO): δ 3.62-3.71 (m, 2H), 4.14-4.19 (m, 1H), 4.25-4.47 (m,1H), 4.47-4.50 (m, 1H), 5.13 (t, 1H), 7.10 (d, 1H), 7.12-7.78 (m, 2H).

Methanesulfonic acid (R)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethylester

(S)-2-[(R*)-3-(3-Hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol(2.84 mmol, 0.60 g) was dissolved in dry dichloromethane. Triethylamine(0.43 ml) was added and the mixture was cooled to 0° C. Methanesulfonylchloride (2.94 mmol, 0.34 g) was added drop wise at 0° C. The mixturewas allowed to warm to RT and stirred over night. 1M Hydrogen chloridesolution (10 ml) was added. Water phase was extracted twice with DCM andthe organic phases were combined. The organic phase was extracted withwater and brine and evaporated to dryness. The crude product waspurified by crystallization (EtOH) to give 0.48 g of the title compound.

¹H NMR (CDCl₃): δ 3.11 (s, 3H), 4.19-4.24 (m, 1H), 4.43-4.54 (m, 4H),6.69 (d, 1H), 7.81-7.84 (m, 2H).

3-[(R)-1-((S)-7-Nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol

Methanesulfonic acid (R)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethylester (0.98 mmol, 0.28 g) was dissolved in the mixture of DMF (2.8 ml)and acetonitrile (2.8 ml). NaHCO₃ (2.92 mmol, 0.25 g) and(R*)-3-(piperidin-3-yl) phenol hydrochloride was added. The mixture wasrefluxed 4 h and after cooling water (15 ml) was added. The water phasewas extracted twice with ethyl acetate and washed with water and brine.Evaporation to dryness gave 0.36 g of the crude product. Flashchromatography, using heptane/EtOAc as eluent and crystallisation(CHCl₃) gave 83 mg of the desired product.

¹H NMR (CDCl₃): δ 1.25-1.28 (m, 1H), 1.72-1.78 (m, 2H), 1.92-1.94 (m,1H), 2.16-2.25 (m, 2H), 2.61-2.83 (m, 3H), 2.95-3.07 (m, 2H), 4.09 (dd,1H), 4.33-4.34 (m, 1H), 4.42 (dd, 1H), 4.94 (s, 1H), 6.66-6.73 (m, 2H),6.80 (d, 1H), 6.91-6.95 (m, 1H), 7.17 (t, 1H), 7.75-7.78 (m, 2H). Asalready mentioned hereinbefore, the compounds of formula I showinteresting pharmacological properties, namely they exhibit an improvedselectivity for the alpha2C adrenoceptor subtype and/or an enhancedpotency. Said properties are demonstrated with the pharmacological testpresented below.

Experiment 1: Determination of Alpha2A and Alpha2C Antagonistic ActivityIn Vitro

Chinese hamster ovary (CHO) cells stably transfected with human alpha2Aand alpha2C or rodent alpha2D receptors (University of Turku, Finland)were cotransfected with the expression vector pCEP-Ga16 (MolecularDevices, CA, USA) and CHO cells stably transfected with human adrenergicalpha2B receptors and mitochondrially targeted aequorin (Euroscreen,Belgium) were used in this experiment. The cells were maintained at 37°C. in a 5% CO₂/95% air atmosphere. The cells were cultured in HAM F-12medium supplemented with 10% FCS, 25 mM HEPES, 100 IU/ml penicillin, 100μg/ml streptomycin, 500 μg/ml geneticin and 240 μg/ml hygromycin B. Thecells were subcultured twice weekly with 0.25% trypsin and 1 mM EDTA.The subculture ratio was 1:5-1:20. The growth medium was changed every 2or 3 days. All cell culture reagents were from Gibco. The day before theexperiment the cells were plated into black-walled, clear bottom 96-wellplates at a density of 30,000-45,000 cells/well.

The growth medium was removed and the cells were incubated with the testcompounds and the FLIPR Calcium 3 Assay reagent (Molecular Devices, CA,USA) for 1 h at 37° C. in dark. The test compounds (concentrations incells 100 μM-10 μM) were dissolved in Probenecid-Ringer consisting of150 mM NaCl, 3 mM KCl, 1.2 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose, 20 mMHEPES and 2.5 mM probenecid (pH 7.4 adjusted with 1.0 M NaOH). Theosmolarity was adjusted to 322 milliosmoles with Osmostat® OM-6020osmometer (DIC Kyoto Daiichi Kagagu Co. Ltd, Japan). The changes inintracellular calcium were monitored using FLEXstation benchtop scanningfluorometer with integrated fluid transfer workstation (MolecularDevices, CA, USA) and displayed using SOFTmax PRO version 3.2 software.All experiments were performed at 37° C. The test compounds dissolved inProbenecid-Ringer were applied by FLEX station at 17 s time point. TheIC₅₀ value for a given test compound was determined from dose-responsecurves, which ranged from 0.01 nM to 10 μM. In order to determineantagonism, the cells were stimulated either with 100 nM adrenaline or200 nM noradrenaline and the test compounds were added to the cells atleast 5 mM before the experiment. Typically, there were four replicatesat each concentration and seven different dose levels. For example, ifthe number of plates from which results were obtained was three, 84(4*7*3) wells were thus measured to construct dose-responserelationship. The samples were excited at 485 nm and emission wasdetected at 525 nm with a 515 nm cut-off filter. Reading time was 60 sper well and the photomultiplier sensitivity value was set to 15. Theminimum fluorescence value subtracted from the maximum value for eachwell was used in the calculations. SOFTmax PRO version 3.2 software wasused for analyzing the results. Fitting of the antagonist dose-responseresults was performed with the free Hill equation and the IC₅₀ valueswere fitted with Michaelis-Menten equation in Sigma Plot 8.0.

The results are shown in Table 1.

TABLE 1 Alpha2A and alpha2C antagonistic activity in vitro. IC₅₀/nMCompound Alpha2A Alpha2C Compound of example 2 3780.6 11.4 Compound ofexample 12 374.1 19.6 Compound of example 18 >10000 69.5 Compound ofexample 29 4357.3 5.4 Compound of example 48 1470.4 7.4 Compound ofexample 58 776.2 9.5 Compound of example 61 2874.0 2.4 Compound ofexample 63 2726.4 0.8 Compound of example 69 1286.2 1.7 Compound ofexample 71 1154.0 1.1 Compound of example 72 635.4 0.9 Compound ofexample 74 345.7 7.4 Compound of example 86 8423.6 10.7 Compound ofexample 89 2141.0 0.6 Compound of example 96 5444.6 4.6

In vivo effects of the compounds of formua I can be demonstrated withthe pharmacological tests as described in WO 03/082866.

The compounds of formula I exhibit alpha2C antagonistic activity. Thepresent invention thus provides compounds for use as a medicament.Compounds for use in the treatment of diseases or conditions where analpha2C antagonist is indicated to be useful are also provided.Furthermore, a method for the treatment of diseases or conditions wherean alpha2C antagonist is indicated to be useful is provided. In saidmethod an effective amount of at least one compound of formula I isadministered to a mammal, e.g. human, in need of such treatment. The useof the compounds of formula I for the manufacture of a medicament forthe treatment of diseases or conditions where an alpha2C antagonist isindicated to be useful is also provided.

In one embodiment of the invention the aforementioned disease orcondition where an alpha2C antagonist is indicated to be useful is amental disorder propagated by stress, Parkinson's disease, depression,schizophrenia, attention deficit hyperactivity disorder, post-traumaticstress disorder, obsessive compulsive disorder, Tourette's syndrome,blepharospasm or other focal dystonias, temporal lobe epilepsy withpsychosis, a drug-induced psychosis, Huntington's disease, a disordercaused by fluctuation of the levels of sex hormones, panic disorder,Alzheimer's disease or mild cognitive impairment; for example, a mentaldisorder propagated by stress, Parkinson's disease, depression,schizophrenia, attention deficit hyperactivity disorder, obsessivecompulsive disorder or Alzheimer's disease; such as a mental disorderpropagated by stress, depression or schizophrenia.

Representative examples of drug-induced psychoses include, but are notlimited to, psychosis caused by chronic use of dopaminergic agents.

Representative examples of disorders caused by fluctuation of the levelsof sex hormones include, but are not limited to, premenstrual syndromeand hot flashes.

The compounds of the invention can be administered, for example,enterally, topically or parenterally by means of any pharmaceuticalformulation useful for said administration and comprising at least oneactive compound of formula I in pharmaceutically acceptable andeffective amounts together with pharmaceutically acceptable diluents,carriers and/or excipients known in the art. The manufacture of suchpharmaceutical formulations is known in the art.

The therapeutic dose to be given to a subject in need of the treatmentwill vary depending on the compound being administered, the species, theage and the sex of the subject being treated, the particular conditionbeing treated, as well as the route and method of administration, and iseasily determined by a person skilled in the art. Accordingly, thetypical dosage for oral administration is from 10 ng/kg to 100 mg/kg perday and for parenteral administration from 1 ng/kg to 10 mg/kg for anadult mammal.

The compounds of the invention are given to the subject as such or incombination with one or more other active ingredients, each in its owncomposition or some or all of the active ingredients combined in asingle composition, and/or suitable pharmaceutical excipients. Suitablepharmaceutical excipients include conventionally used excipients andformulation aids, such as fillers, binders, disintegrating agents,lubricants, solvents, gel forming agents, emulsifiers, stabilizers,colorants and/or preservatives.

The compounds of the invention are formulated into dosage forms usingcommonly known pharmaceutical manufacturing methods. The dosage formscan be, for example, tablets, capsules, granules, suppositories,emulsions, suspensions or solutions. Depending on the route ofadministration and the galenic form, the amount of the active ingredientin a formulation can typically vary between 0.01% and 100% by weight.

A person skilled in the art will appreciate that the embodimentsdescribed in this application can be modified without departing from theinventive concept. A person skilled in the art also understands that theinvention is not limited to the particular embodiments disclosed but isintended to also cover modifications of the embodiments that are withinthe scope of the invention.

1-39. (canceled)
 40. A compound of formula I,

wherein X is C(R₅)(R₆) or C(R₇)(R₈); z is —[C(R₄)₂]_(n); R₁ is ahalogen; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is phenyl substitutedwith 1 substituent R₉; R₇ is (C₁-C₆)alkyl; R₈ is hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy or (C₁-C₆)alkoxy-(C₁-C₆)alkoxy; R₉ is,independently at each occurrence, hydroxy, (C₁-C₆)alkoxy, halogen,hydroxy(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkoxy; m is 0 or 1; and n is 1;or a pharmaceutically acceptable salt thereof.
 41. The compound of claim40, wherein the compound is(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidineor a pharmaceutically acceptable salt thereof.
 42. The compound of claim40, wherein the compound is(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidineor a pharmaceutically acceptable salt thereof.
 43. The compound of claim40, wherein the compound is(R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenolor a pharmaceutically acceptable salt thereof.
 44. The compound of claim40, wherein the compound is(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanolor a pharmaceutically acceptable salt thereof.
 45. The compound of claim40, wherein the compound is2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanolor a pharmaceutically acceptable salt thereof.
 46. The compound of claim40, wherein the compound is3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-olor a pharmaceutically acceptable salt thereof.
 47. The compound of claim40, wherein the compound is(R*)-3-[1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenolor a pharmaceutically acceptable salt thereof.
 48. The compound of claim40, wherein the compound is{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanolor a pharmaceutically acceptable salt thereof.
 49. The compound of claim40, wherein the compound is2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanolor a pharmaceutically acceptable salt thereof.
 50. The compound of claim40, wherein the compound is(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidineor a pharmaceutically acceptable salt thereof.